Download Neurobiology of injury to the developing brain.

Exp Neurol. 2010 Oct 18. [Epub ahead of print]
Pioglitazone attenuates mitochondrial
dysfunction, cognitive impairment, cortical
tissue loss, and inflammation following
traumatic brain injury.
Sauerbeck A, Gao J, Readnower R, Liu M, Pauly JR, Bing G, Sullivan P.
Department of Anatomy and Neurobiology, University of Kentucky, 741. S Limestone St.,
BBSRB, Room 436, Lexington, Ky 40536; Spinal Cord and Brain Injury Research Center,
University of Kentucky, 741. S Limestone St., BBSRB, Room 436, Lexington, Ky 40536.
Abstract
Following traumatic brain injury (TBI) there is significant neuropathology which includes
mitochondrial dysfunction, loss of cortical grey matter, microglial activation, and cognitive
impairment. Previous evidence has shown that activation of the peroxisome proliferatoractivated receptors (PPARs) provide neuroprotection following traumatic brain and spinal
injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone
would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals
received a unilateral 1.5mm controlled cortical impact followed by administration of
pioglitazone at 10mg/kg beginning 15 minutes after the injury and subsequently every 24hrs for
five days. Beginning one day after the injury there was significant impairment in mitochondrial
bioenergetic function which was attenuated by treatment with Pioglitazone at 15 minutes and 24
hours (p<0.05). In an additional set of animals, cognitive function was assessed using the Morris
Water Maze (MWM) and it was observed that over the course of four days of testing the injury
produced a significant increase in both latency (p<0.05) and distance (p<0.05) to the platform.
Animals treated with Pioglitazone performed similarly to sham animals and did not exhibit any
impairment in MWM performance. Sixteen days after the injury tissue sections through the
lesion site were quantified to determine the size of the cortical lesion. Vehicle treated animals
had an average lesion size of 5.09±0.73mm(3) and treatment with Pioglitazone significantly
reduced the lesion size by 55% to 2.27±0.27mm(3) (p<0.01). Co-administration of the antagonist
T0070907 with Pioglitazone blocked the protective effect seen with administration of
Pioglitazone by itself. Following the injury there was a significant increase in the number of
activated microglia in the area of the cortex adjacent to the site of the lesion (p<0.05). Treatment
with Pioglitazone prevented the increase in the number of activated microglia and no difference
was observed between sham and Pioglitazone treated animals. From these studies we conclude
that following TBI Pioglitazone is capable ameliorating multiple aspect of neuropathology.
These studies provide further support for the use of PPAR ligands, specifically Pioglitazone, for
neuroprotection.
Copyright © 2010. Published by Elsevier Inc.
PMID: 20965168 [PubMed - as supplied by publisher]
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Brain Res. 2010 Oct 14. [Epub ahead of pint]
Synergism of Human Amnion-derived
Multipotent Progenitor (AMP) Cells and a
Collagen Scaffold in Promoting Brain Wound
Recovery: Pre-clinical Studies in an
Experimental Model of Penetrating Ballisticlike Brain Injury.
Chen Z, Lu XC, Shear DA, Dave JR, Davis AR, Evangelista CA, Duffy D, Tortella FC.
Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed
Army Institute of Research, Silver Spring, MD 20910.
Abstract
One of the histopathological consequences of a penetrating ballistic brain injury is the formation
of a permanent cavity. In a previous study using the penetrating ballistic-like brain injury (PBBI)
model, engrafted Human Amnion-derived Multipotent Progenitor (AMP) cells failed to survive
when injected directly in the injury tract, suggesting that the cell survival requires a supportive
matrix. In this study, we seated AMP cells in a collagen-based scaffold, injected into the injury
core, and investigated cell survival and neuroprotection following PBBI. AMP cells suspended in
AMP Cell Conditioned Medium (ACCS) or in a liquefied collagen matrix were injected
immediately after a PBBI along the penetrating injury tract. Injured control rats received only
liquefied collagen matrix. All animals were allowed to survive two weeks. Consistent with our
previous results AMP cells suspended in ACCS failed to survive; likewise, no collagen was
identified at the injury site when injected alone. In contrast, both AMP cells and the collagen
were preserved in the injury cavity when injected together. In addition, AMP cells/collagen
treatment preserved some apparent brain tissue in the injury cavity, and there was measurable
infiltration of endogenous neural progenitor cells and astrocytes into the preserved brain tissue.
AMP cells were also found to have migrated into the subventricular zone and the corpus
callosum. Moreover, the AMP cell/collagen treatment significantly attenuated the PBBI-induced
axonal degeneration in the corpus callosum and ipsilateral thalamus and improved motor
impairment on rotarod performance. Overall, collagen-based scaffold provided a supportive
matrix for AMP cell survival, migration, and neuroprotection.
Copyright © 2010. Published by Elsevier B.V.
PMID: 20951684 [PubMed - as supplied by publisher]
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J Neurosci Res. 2010 Oct 8. [Epub ahead of print]
Green tea polyphenols potentiate the action
of nerve growth factor to induce
neuritogenesis: Possible role of reactive
oxygen species.
Gundimeda U, McNeill TH, Schiffman JE, Hinton DR, Gopalakrishna R.
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern
California, Los Angeles, California.
Abstract
Exogenously administered nerve growth factor (NGF) repairs injured axons, but it does not cross
the blood-brain barrier. Thus, agents that could potentiate the neuritogenic ability of endogenous
NGF would be of great utility in treating neurological injuries. Using the PC12 cell model, we
show here that unfractionated green tea polyphenols (GTPP) at low concentrations (0.1 μg/ml)
potentiate the ability of low concentrations of NGF (2 ng/ml) to induce neuritogenesis at a level
comparable to that induced by optimally high concentrations of NGF (50 ng/ml) alone. In our
experiments, GTPP by itself did not induce neuritogenesis or increase immunofluorescent
staining for β-tubulin III; however, it increased expression of mRNA and proteins for the
neuronal markers neurofilament-L and GAP-43. Among the polyphenols present in GTPP,
epigallocatechin-3-gallate (EGCG) alone appreciably potentiated NGF-induced neurite
outgrowth. Although other polyphenols present in GTPP, particularly epigallocatechin and
epicatechin, lack this activity, they synergistically promoted this action of EGCG. GTPP also
induced an activation of extracellular signal-regulated kinases (ERKs). PD98059, an inhibitor of
the ERK pathway, blocked the expression of GAP-43. K252a, an inhibitor of TrkA-associated
tyrosine kinase, partially blocked the expression of these genes and ERK activation.
Antioxidants, catalase (cell-permeable form), and N-acetylcysteine (both L and D-forms)
inhibited these events and abolished the GTPP potentiation of NGF-induced neuritogenesis.
Taken together, these results show for the first time that GTPP potentiates NGF-induced
neuritogenesis, likely through the involvement of sublethal levels of reactive oxygen species, and
suggest that unfractionated GTPP is more effective in this respect than its fractionated
polyphenols. © 2010 Wiley-Liss, Inc.
PMID: 20936703 [PubMed - as supplied by publisher]
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J Neurotrauma. 2010 Oct 1. [Epub ahead of print]
Human traumatic brain injury alters plasma
microRNA levels.
Redell JB, Moore AN, Ward Iii NH, Hergenroeder GW, Dash PK.
University of Texas Health Science Center-Houston, Neurobiology and Anatomy, 6431 Fannin,
Houston, Texas, United States, 77030; [email protected].
Abstract
Circulating microRNAs (miRNAs) present in the serum/plasma are characteristically altered in
many pathological conditions, and have been employed as diagnostic markers for specific
diseases. We examined if relative plasma miRNA levels are altered in patients with traumatic
brain injury (TBI) as compared to matched healthy volunteers, and their potential for use as
diagnostic TBI biomarkers. The plasma miRNA profiles from severe TBI patients (GCS
&#x2264; 8) and age-, gender-, and race-matched healthy volunteers were compared by
microarray analysis. Of the 108 miRNAs identified in healthy volunteer plasma, 52 were altered
after severe TBI, including 33 with decreased and 19 with increased relative abundance. An
additional 8 miRNAs were detected only in the TBI plasma. We used quantitative RT-PCR to
determine if circulating miRNAs could segregate TBI patients within the first 24 hr post-injury.
Receiver Operating Characteristic analysis indicated that miR-16, miR-92a and miR-765 were
good markers of severe TBI (0.89, 0.82, and 0.86 AUC values, respectively). Multiple logistic
regression analysis revealed that combining these miRNAs markedly increased diagnostic
accuracy (100% specificity and 100% sensitivity) compared to either healthy volunteers or
orthopedic injury patients. In mild TBI patients (GCS&gt;12), miR-765 levels were unchanged,
while the levels of miR-92a and miR-16 were significantly increased within the first 24 hr of
injury compared to healthy volunteers, and had AUC values of 0.78 and 0.82, respectively. Our
results demonstrate that circulating miRNA levels are altered after TBI, providing a rich new
source of potential molecular biomarkers. Plasma-derived miRNA biomarkers, used in
combination with established clinical practices such as imaging, neurocognitive, and motor
examinations, have the potential to improve TBI patient classification and possibly management.
PMID: 20883153 [PubMed - as supplied by publisher]
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J Mol Neurosci. 2010 Sep 21. [Epub ahead of print]
Cortical 5HT(2A) Receptor Function under
Hypoxia in Neonatal Rats: Role of Glucose,
Oxygen, and Epinephrine Resuscitation.
Anju TR, Smijin S, Korah PK, Paulose CS.
Molecular Neurobiology and Cell Biology Unit, Center for Neuroscience, Department of
Biotechnology, Cochin University of Science and Technology, Cochin, 682022, Kerala, India.
Abstract
Neonatal hypoxia induces brain injury through alterations in neurotransmitters and its receptors.
Molecular processes regulating serotonergic receptors play an important role in the control of
respiration under hypoxia. The present study evaluates the serotonergic regulation of neonatal
hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were
done to evaluate the changes in 5HT(2A) receptors and its transporter in the cerebral cortex of
hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine.
Hypoxic stress increased total 5HT and 5HT(2A) receptor number along with an upregulation of
5HT(2A) receptor and 5HT transporter gene in the cortex. The enhanced cortical 5HT(2A)
receptors may act as a modulator of ventilatory response to hypoxia. These alterations were
reversed to near control by glucose supplementation. Glucose supplementation helped in
managing the serotonergic functional alterations. Hypoxia-induced adenosine triphosphate
depletion causes a reduction in blood glucose levels which can be encountered by glucose
administration, and oxygenation helps in overcoming the anaerobic condition. The adverse effect
of immediate oxygenation and epinephrine supplementation was also reported. This has immense
clinical significance in establishing a proper resuscitation for the management of neonatal
hypoxia.
PMID: 20857344 [PubMed - as supplied by publisher]
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Brain Res. 2010 Sep 17. [Epub ahead of print]
Alterations of NMDA receptor subunits NR1,
NR2A and NR2B mRNA expression and their
relationship to apoptosis following transient
forebrain ischemia.
Liu Z, Zhao W, Xu T, Pei D, Peng Y.
Department of Anatomy, Nanjing Medical University, Nanjing 210029, China; Department of
Anatomy and Neurobiology, Xuzhou Medical College, Xuzhou 221002, China.
Abstract
Glutamate excitotoxicity mediated by NMDA receptor activation plays a key role in many
aspects of ischemic brain injury, but the expression of NMDA receptor subunits NR1, NR2A and
NR2B mRNA and their relationship to apoptosis is still unclear. In this study, we applied in situ
hybridization and TUNEL staining to investigate the expression of NMDA receptor subunit
mRNA and apoptosis in hippocampus of rats after transient forebrain ischemia. The results
showed that in the CA1 region, NR1 mRNA expression was significantly increased following
ischemia-reperfusion (IR), reaching peak levels at IR 24h, and then gradually decreasing until IR
7days. NR2A and NR2B mRNA expression dropped to lowest levels at IR 6h and IR 12h,
respectively, and then started to recover. The mRNA expression of both NR2A and NR2B then
increased to peak levels at IR 48h, followed by a sustained decline until IR 7days. In the CA3
region and dentate gyrus the range of variation in mRNA expression was significantly reduced
gradually. At IR 24h, apoptosis-positive cells were observed mainly in the CA1 region. The
number of apoptosis-positive cells continuously grew and showed a dramatic increase at IR 48h
and peaked at IR 72h. Then, the number of apoptosis-positive cells started to decrease, but at IR
7days the apoptosis-positive cells still remained. These results indicate that the alterations of
NMDA receptor subunit mRNA expression may contribute to the ischemic apoptosis of
hippocampus after transient forebrain ischemia.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20850419 [PubMed - as supplied by publisher]
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#3J Neurotrauma. 2010 Oct 18. [Epub ahead of print]
Association of Chronic Vascular Changes
with Functional Outcome after Traumatic
Brain Injury in Rats.
Hayward NM, Immonen R, Tuunanen PI, Ndode-Ekane XE, Gröhn O, Pitkänen A.
1 Department of Neurobiology, Biomedical NMR Group, A. I. Virtanen Institute for Molecular
Sciences, University of Eastern Finland , Kuopio, Finland .
Abstract
Abstract We tested the hypothesis that vascular remodeling in the cortex, hippocampus, and
thalamus is associated with long-term functional recovery after traumatic brain injury (TBI). We
induced TBI with lateral fluid-percussion (LFP) injury in adult rats. Animals were followed-up
for 9 months, during which we tested motor performance using a neuroscore test, spatial learning
and memory with a Morris water maze, and seizure susceptibility with a pentylenetetrazol (PTZ)
test. At 8 months, they underwent structural MRI, and cerebral blood flow (CBF) was assessed
by arterial spin labeling (ASL) MRI. Then, rats were perfused for histology to assess the density
of blood vessels. In the perilesional cortex, the CBF decreased by 56% (p < 0.01 compared to
controls), and vessel density increased by 28% (p < 0.01). There was a negative correlation
between CBF in the perilesional cortex and vessel density (r = -0.75, p < 0.01). However, in the
hippocampus, we found a 13% decrease in CBF ipsilaterally (p < 0.05) and 20% contralaterally
(p < 0.01), and no change in vessel number. In the ipsilateral thalamus, the increase in CBF
(34%, p < 0.01) was associated with a remarkable increase in vessel density (78%, p < 0.01).
Animals showed motor impairment that was not associated with vascular changes. Instead, poor
performance in the Morris water maze correlated with enhanced thalamic vessel density (r = 0.81, p < 0.01). Finally, enhanced seizure susceptibility was associated with reduced CBF in the
ipsilateral hippocampus (r = 0.78, p < 0.05) and increased vascular density in the thalamus
(r = 0.69, p < 0.05). There was little interaction between the behavioral measures. The present
study demonstrates that each of the investigated brain areas has a unique pattern of vascular
abnormalities. Chronic alterations in CBF could not be attributed to changes in vascular density.
Association of thalamic hypervascularity to epileptogenesis warrants further studies. Finally,
hippocampal hypoperfusion may predict later seizure susceptibility in the LFP injury model of
TBI, which could be of value for pre-clinical antiepileptogenesis trials.
PMID: 20839948 [PubMed - as supplied by publisher]
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================Arch Neurol. 2010 Sep;67(9):1068-73.
New perspectives on amyloid-beta dynamics
after acute brain injury: moving between
experimental approaches and studies in the
human brain.
Magnoni S, Brody DL.
Washington University, St Louis, MO 63110, USA.
Abstract
The links between traumatic brain injury and Alzheimer disease have been of great interest for
many years. However, the importance of amyloid-β-related neurodegenerative pathophysiologic
processes after traumatic brain injury is still unknown. In this review, we present a brief
overview of the scientific evidence regarding traumatic brain injury as a contributor to
Alzheimer disease and describe recent results showing significant changes in brain extracellular
amyloid-β dynamics in patients with severe brain injury. We then discuss the clinical
significance of these findings with their implications for translational neurobiology and conclude
with further directions for traumatic brain injury and Alzheimer disease research.
PMID: 20837849 [PubMed - indexed for MEDLINE]
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================Neuropathol Appl Neurobiol. 2010 Aug 31. doi: 10.1111/j.13652990.2010.01117.x. [Epub ahead of print]
Combined NgR Vaccination and Neural Stem
Cell Transplantation Promote Functional
Recovery after Spinal Cord Injury in Adult
Rats.
Xu CJ, Xu L, Huang LD, Li Y, Yu PP, Hang Q, Xu XM, Lu PH.
Department of Neurobiology Shanghai Jiao Tong University School of Medicine Shanghai
200025, P.R. China Spinal Cord and Brain Injury Research Group Stark Neurosciences
Research Institute and Department of Neurological Surgery Indiana University School of
Medicine Indianapolis, IN 46202, U.S.A.
Abstract
Aims: After spinal cord injury (SCI), there are many adverse factors at the lesion site such as
glial scar, myelin-derived inhibitors, cell loss, and deficiency of neurotrophins that impair axonal
regeneration. Therefore, combination therapeutic strategies might be more effective than a single
strategy for promoting functional recovery after SCI. In the present study, we investigated
whether a NgR vaccine, combined with neural stem cell (NSC) transplantation, could promote
better functional recovery than when NgR vaccine or NSCs were used alone. Methods: Adult
rats were immunized with NgR vaccine at 1 week after a contusive SCI at the thoracic level, and
the NSCs, obtained from green fluorescent protein (GFP) transgenic rats, were transplanted into
the injury site at 8 weeks post-injury. The functional recovery of the animals under various
treatments was evaluated by three independent behavioral tests, i.e. BBB locomotor rating scale,
footprint analysis, and grid walking. Results: The combined therapy with NgR vaccination and
NSC transplantation protected more ventral horn motor neurons in the injured spinal cord and
greater functional recovery than when they were used alone. Furthermore, NgR vaccination
promoted migration of engrafted NSCs along the rostral-caudal axis of the injured spinal cords,
and induced their differentiation into neurons and oligodendrocytes in vivo. Conclusions: The
combination therapy of NgR vaccine and NSC transplantation exhibited significant advantages
over any single therapy alone in this study. It may represent a potential new therapy for spinal
cord injury.
© 2010 Radboud University Nijmegen Medical Centre.
PMID: 20819171 [PubMed - as supplied by publisher]
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================PLoS One. 2010 Aug 18;5(8):e12272.
Human neural stem cells differentiate and
promote locomotor recovery in an early
chronic spinal cord injury NOD-scid mouse
model.
Salazar DL, Uchida N, Hamers FP, Cummings BJ, Anderson AJ.
Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California,
United States of America.
Abstract
BACKGROUND: Traumatic spinal cord injury (SCI) results in partial or complete paralysis and
is characterized by a loss of neurons and oligodendrocytes, axonal injury, and
demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have
chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant.
Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescenceactivated cell sorting for a CD133(+) and CD24(-/lo) population from fetal brain, grown as
neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes.
hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found
to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30
days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.
METHODS AND FINDINGS: hCNS-SCns were transplanted into immunodeficient NOD-scid
mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated
significantly improved locomotor recovery compared to vehicle controls using open field
locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term
engraftment, migration, limited proliferation, and differentiation predominantly to
oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit
mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as
demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal
marker contactin-associated protein.
CONCLUSIONS: The results suggest that hCNS-SCns are capable of surviving, differentiating,
and promoting improved locomotor recovery when transplanted into an early chronic injury
microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early
chronic SCI setting and thus expands the "window of opportunity" for intervention.
PMID: 20806064 [PubMed - in process]PMCID: PMC2923623Free PMC Article
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================J Neurochem. 2010 Nov;115(4):910-20. doi: 10.1111/j.14714159.2010.06960.x. Epub 2010 Sep 28.
OKEY
Bex1 is involved in the regeneration of axons
after injury.
Khazaei MR, Halfter H, Karimzadeh F, Koo JH, Margolis FL, Young P.
Department of Neurology, University Hospital of Münster, Münster, Germany Institute of
General Zoology and Genetics, Westfalian Wilhelms University, Münster, Germany Department
of Anatomy and Neurobiology, School of Medicine, University of Maryland Baltimore,
Baltimore, Maryland, USA.
Abstract
J. Neurochem. (2010) 115, 910-920. ABSTRACT: Successful axonal regeneration is a complex
process determined by both axonal environment and endogenous neural capability of the
regenerating axons in the central and the peripheral nervous systems. Numerous external
inhibitory factors inhibit axonal regeneration after injury. In response, neurons express various
regeneration-associated genes to overcome this inhibition and increase the intrinsic growth
capacity. In the present study, we show that the brain-expressed X-linked (Bex1) protein was
over-expressed as a result of peripheral axonal damage. Bex1 antagonized the axon outgrowth
inhibitory effect of myelin-associated glycoprotein. The involvement of Bex1 in axon
regeneration was further confirmed in vivo. We have demonstrated that Bex1 knock-out mice
showed lower capability for regeneration after peripheral nerve injury than wild-type animals.
Wild-type mice could recover from sciatic nerve injury much faster than Bex1 knock-out mice.
Our findings suggest that Bex1 could be considered as regeneration-associated gene.
© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for
Neurochemistry.
PMID: 20731761 [PubMed - in process]
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================Brain. 2010 Sep;133(9):2519-27. Epub 2010 Aug 18.
Multiple chronic pain states are associated
with a common amino acid-changing allele in
KCNS1.
Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk C, Poddar
M, Lu Y, Diatchenko L, Smith S, Cobos EJ, Zaykin D, Allchorne A, Shen PH, Nikolajsen L,
Karppinen J, Männikkö M, Kelempisioti A, Goldman D, Maixner W, Geschwind DH, Max MB,
Seltzer Z, Woolf CJ.
F.M. Kirby Neurobiology Centre, Children’s Hospital Boston and Harvard Medical School,
Boston, MA 02115, USA.
Comment in:

Brain. 2010 Sep;133(9):2515-8.
Abstract
Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age
at the time of injury are two of the few risk factors identified to date. In addition, preclinical
studies show that neuropathic pain variance is heritable. To define such factors further, we
performed a large-scale gene profiling experiment which plotted global expression changes in
the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the
discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is
constitutively expressed in sensory neurons and markedly downregulated following nerve injury.
KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result
confirmed by single nucleotide polymorphism association studies in humans. A common amino
acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores
in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence
is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At
lower levels of nerve damage (lumbar back pain with disc herniation) association with greater
pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of
nerve injury (limb amputation). The combined P-value for pain association in all six cohorts
tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one
intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but
for patients with lumbar back pain, they range between 2- and 3-fold. Although work still
remains to define the potential role of this protein in the pathogenic process, here we present the
KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening
for this allele could help define those individuals prone to a transition to persistent pain, and thus
requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
PMID: 20724292 [PubMed - indexed for MEDLINE]PMCID: PMC2929335 [Available on
2011/9/1]
=====================================================================================
OKEY
Biochem Biophys Res Commun. 2010 Sep 3;399(4):694-8. Epub 2010 Aug 5.
Distribution of radiolabeled l-glutamate and
d-aspartate from blood into peripheral
tissues in naive rats: significance for brain
neuroprotection.
Klin Y, Zlotnik A, Boyko M, Ohayon S, Shapira Y, Teichberg VI.
Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract
Excess l-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF,
respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic
brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate
excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have
established the role of blood glutamate levels in brain neuroprotection, we have now investigated
the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have
administered naive rats with intravenous injections of either l-[1-(14)C] Glutamic acid (l-[1(14)C] Glu), l-[G-(3)H] Glutamic acid (l-[G-(3)H] Glu) or d-[2,3-(3)H] Aspartic acid (d-[2,3(3)H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into
peripheral organs. We have observed that the decay of the radioactivity associated with l-[1(14)C] Glu and l-[G-(3)H] Glu was faster than that associated with glutamate non-metabolized
analog, d-[2,3-(3)H] Asp. l-[1-(14)C] Glu was subjected in blood to a rapid decarboxylation with
the loss of (14)CO(2). The three major sequestrating organs, serving as depots for the eliminated
glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92%
or 87% of total l-[U-(14)C] Glu or d-[2,3-(3)H] Asp radioactivity capture. l-[U-(14)C] Glu and
d-[2,3-(3)H] Asp showed a different organ sequestration pattern. We conclude that glutamate is
rapidly eliminated from the blood into peripheral tissues, mainly in non-metabolized form. The
liver plays a central role in glutamate metabolism and serves as an origin for glutamate
metabolites that redistribute into skeletal muscle and gut. The findings of this study suggest now
that pharmacological manipulations that reduce the liver glutamate release rate or cause a
boosting of the skeletal muscle glutamate pumping rate are likely to cause brain neuroprotection.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20691657 [PubMed - indexed for MEDLINE]
=====================================================================================
J Neurotrauma. 2010 Oct;27(10):1911-23. Epub 2010 Oct 6.
Longitudinal characterization of motor and
cognitive deficits in a model of penetrating
ballistic-like brain injury.
Shear DA, Lu XC, Bombard MC, Pedersen R, Chen Z, Davis A, Tortella FC.
Walter Reed Army Institute of Research, Department of Applied Neurobiology, Silver Spring,
Maryland 20910, USA. [email protected]
Abstract
Traumatic brain injury (TBI) produces a wide range of motor and cognitive changes. While some
neurological symptoms may respond to therapeutic intervention during the initial recovery
period, others may persist for many years after the initial insult, and often have a devastating
impact on quality of life for the TBI victim. The aim of the current study was to develop
neurobehavioral testing parameters designed to provide a longitudinal assessment of
neurofunctional deficits in a rodent model of penetrating ballistic-like brain injury (PBBI). We
report here a series of experiments in which unilateral frontal PBBI was induced in rats, and
motor/cognitive abilities were assessed using a battery of tests ranging from 30 min to 10 weeks
post-injury. The results showed that PBBI produced consistent and significant (1) neurological
deficits (neuroscore examination: 30 min to 10 weeks post-PBBI), (2) sensorimotor dysfunction
in the contralateral forelimb (forelimb asymmetry task: 7 and 21 days), (3) motor dysfunction
(balance beam task: 3-7 days; and fixed-speed rotarod task: 3-28 days), and (4) spatial learning
deficits in the Morris water maze (MWM) task out to 10 weeks post-injury. Overall, the results
of this study demonstrate that PBBI produces enduring motor and cognitive deficits, and
identifies the optimal task and testing parameters for facilitating longitudinal screening of
promising therapeutic interventions in this brain injury model.
PMID: 20684676 [PubMed - in process]
=====================================================================================
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14413-8. Epub 2010 Jul 26.
Sniffing enables communication and
environmental control for the severely
disabled.
Plotkin A, Sela L, Weissbrod A, Kahana R, Haviv L, Yeshurun Y, Soroker N, Sobel N.
Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Comment in:


Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):13979-80.
Nat Rev Neurol. 2010 Oct;6(10):528.
Abstract
Paradoxically, improvements in emergency medicine have increased survival albeit with severe
disability ranging from quadriplegia to "locked-in syndrome." Locked-in syndrome is
characterized by intact cognition yet complete paralysis, and hence these individuals are "lockedin" their own body, at best able to communicate using eye blinks alone. Sniffing is a precise
sensory-motor acquisition entailing changes in nasal pressure. The fine control of sniffing
depends on positioning the soft palate, which is innervated by multiple cranial nerves. This
innervation pattern led us to hypothesize that sniffing may remain conserved following severe
injury. To test this, we developed a device that measures nasal pressure and converts it into
electrical signals. The device enabled sniffs to control an actuator with speed similar to that of a
hand using a mouse or joystick. Functional magnetic resonance imaging of device usage revealed
a widely distributed neural network, allowing for increased conservation following injury. Also,
device usage shared neural substrates with language production, rendering sniffs a promising
bypass mode of communication. Indeed, sniffing allowed completely paralyzed locked-in
participants to write text and quadriplegic participants to write text and drive an electric
wheelchair. We conclude that redirection of sniff motor programs toward alternative functions
allows sniffing to provide a control interface that is fast, accurate, robust, and highly conserved
following severe injury.
PMID: 20660716 [PubMed - indexed for MEDLINE]PMCID: PMC2922523Free PMC Article
=====================================================================================
Physiol Meas. 2010 Sep;31(9):1075-89. Epub 2010 Jul 23.
Quantification of convection-enhanced
delivery to the ischemic brain.
Haar PJ, Broaddus WC, Chen ZJ, Fatouros PP, Gillies GT, Corwin FD.
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond,
VA, USA.
Abstract
Convection-enhanced delivery (CED) could have clinical application in the delivery of
neuroprotective agents following ischemic stroke. However, ischemic brain tissue changes such
as cytotoxic edema, in which cellular swelling decreases the fractional volume of the
extracellular space, would be expected to significantly alter the distribution of neuroprotective
agents delivered by CED. We sought to predict and characterize these effects using the magnetic
resonance contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a model
therapeutic agent. CED was observed using MRI in a normal rat brain and in a middle cerebral
artery (MCA) occlusion rat model of brain ischemia. Gd-DTPA was infused to the caudate
putamen in the normal rat (n = 6) and MCA occlusion model (n = 6). In each rat, baseline
apparent diffusion coefficient images were acquired prior to infusion, and T1 maps were then
acquired 13 times throughout the duration of the experiment. These T1 maps were used to
compute Gd-DTPA concentrations throughout each brain. In the MCA occlusion group, CED
delivered Gd-DTPA to a comparatively larger volume with lower average tissue concentrations.
Following the infusion, the total content of Gd-DTPA decreased more slowly in the MCA
occlusion group than in the normal group. This quantitative characterization confirms that
edematous ischemic tissue changes alter the distribution of agents by CED. These findings may
have important implications for CED in the treatment of brain injury, and will assist in future
efforts to model the distribution of therapeutic agents.
PMID: 20651424 [PubMed - in process]
Publication Types, Grant Support
=====================================================================
================J Neuroimmunol. 2010 Oct 8;227(1-2):87-92. Epub 2010 Jul 16.
OKEY
CCR7 is expressed in astrocytes and
upregulated after an inflammatory injury.
Gomez-Nicola D, Pallas-Bazarra N, Valle-Argos B, Nieto-Sampedro M.
Neural Plasticity Group, Functional and Systems Neurobiology Department, Cajal Institute,
CSIC, Avda Doctor Arce, 37, 28002, Madrid, Spain. [email protected]
Abstract
Neurodegenerative or autoimmune diseases are frequently regulated by chemokines and their
receptors, controlling both glial activation and immune cell infiltration. CCL19 and CCL21 have
been described to mediate crucial functions during CNS pathological states, regulating both
immune cell traffic to the CNS and communication between glia and neurons. Here, we describe
the expression pattern and cellular sources of CCR7, receptor of CCL19 and CCL21, in the
normal mouse brain. Moreover, we found that CCR7 is upregulated in reactive astrocytes upon
intracerebral LPS, regulating early glial reactivity through its ligands CCL19 and CCL21. Our
results indicate that CCR7 is playing an important role for the intercellular communication
during the inflammatory activation in the CNS.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20638137 [PubMed - indexed for MEDLINE]
=====================================================================
================Ann N Y Acad Sci. 2010 Jun;1199:164-74.
OKEY
Combinatorial techniques for enhancing
neuroprotection: hypothermia and
alkalinization.
Kuffler DP.
Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan.
[email protected]
Abstract
Brain and spinal cord (CNS) trauma typically kill a number of neurons, but even more neurons
are killed by secondary causes triggered by the initial trauma. Thus, a minor insult may rapidly
cause the death of a vastly larger number of neurons and complete paralysis. The best
mechanism for reducing the extent of neurological deficits is to minimize the number of neurons
killed by post-trauma sequelae. Neuroprotection techniques take many diverse forms with a
breadth too great for a short review. Therefore, this review focuses on the neuroprotection
provided by hypothermia and a number of other neuroprotective techniques, when administered
singly or in combination, because it is generally found that combinations of applications lead to
significantly better neuroprotection than is achieved by any one alone. The combinatorial
approach to neuroprotection holds great promise for enhancing the degree of neuroprotection
following trauma, leading to maximum maintenance of neurological function.
PMID: 20633122 [PubMed - indexed for MEDLINE]
=====================================================================
================Neuromolecular Med. 2010 Jul 13. [Epub ahead of print]
OKEY
Dimebon Inhibits Calcium-Induced Swelling
of Rat Brain Mitochondria But Does Not
Alter Calcium Retention or Cytochrome C
Release.
Naga KK, Geddes JW.
Spinal Cord and Brain Injury Research Center, and Department of Anatomy and Neurobiology,
B477 Biomedical & Biological Sciences Research Building (BBSRB), University of Kentucky,
741. S. Limestone Street, Lexington, KY, 40536-0509, USA.
Abstract
Dimebon was originally introduced as an antihistamine and subsequently investigated as a
possible therapeutic for a variety of disorders, including Alzheimer's disease. One putative
mechanism underlying the neuroprotective properties of Dimebon is inhibition of mitochondrial
permeability transition, based on the observation that Dimebon inhibited the swelling of rat liver
mitochondria induced by calcium and other agents that induce permeability transition. Because
liver and brain mitochondria differ substantially in their properties and response to conditions
associated with opening of the permeability transition pore, we sought to determine whether
Dimebon inhibited permeability transition in brain mitochondria. Dimebon reduced calciuminduced mitochondrial swelling but did not enhance the calcium retention capacity or impair
calcium-induced cytochrome C release from non-synaptic mitochondria isolated from rat brain
cerebral cortex. These findings indicate that Dimebon does not inhibit mitochondrial
permeability transition, induced by excessive calcium uptake, in brain mitochondria.
PMID: 20625939 [PubMed - as supplied by publisher]
=====================================================================================
J Stroke Cerebrovasc Dis. 2010 Jul 10. [Epub ahead of print]
OKEY
Eicosapentaenoic Acid Prevents Memory
Impairment After Ischemia by Inhibiting
Inflammatory Response and Oxidative
Damage.
Okabe N, Nakamura T, Toyoshima T, Miyamoto O, Lu F, Itano T.
Department of Neurobiology, Kagawa University Faculty of Medicine, Kagawa, Japan.
Abstract
Previous studies have demonstrated that the generation of reactive oxygen species and an
excessive inflammatory reaction are involved in the progression of neural damage following
brain ischemia. In this study, we focused on the anti-inflammatory and antioxidant properties of
eicosapentaenoic acid (EPA). Gerbils were treated intraperitoneally with 500mg/kg of EPA ethyl
for 4 weeks until the day of forebrain ischemia, which was induced by occluding the bilateral
common carotid artery for 5minutes. In the first part of the 2-part experiment, the effect of EPA
treatment was evaluated using hematoxylin and eosin staining and deoxynucleotidyl transferasemediated dUTP nick-end labeling as a marker of cell death (n=3 per group). The inflammatory
reaction was evaluated using anti-Iba1 immunohistochemistry, a marker of microglial activation
(n=3 per group), and detection of 8-hydroxyl-2'-deoxyguanosine, a marker of oxidative DNA
damage (n=4 per group). In the second part of the experiment, the effect of EPA treatment on
memory function was examined using an 8-arm radial maze (n=6 per group). EPA treatment
significantly inhibited DNA oxidative damage (P < .05) and accumulation of Iba1-positive cells
in the CA1 area at 12 and 72hours after the induction of ischemia, and also decreased apoptotic
neurons and neuronal death (P < .001) at 72hours after ischemia. EPA treatment also
significantly improved memory function (P < .05). These findings suggest that EPA inhibits the
inflammatory reaction and oxidative damage occurring after ischemic brain injury, and also may
contribute to the prevention of neural damage and memory impairment following such injury.
Copyright © 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.
PMID: 20621517 [PubMed - as supplied by publisher]
=====================================================================================
Neuroscience. 2010 Sep 29;170(1):107-16. Epub 2010 Jul 8.
OKEY
The cortical stab injury induces beading of
fibers expressing ecto-nucleoside
triphosphate diphosphohydrolase 3.
Bjelobaba I, Lavrnja I, Parabucki A, Stojkov D, Stojiljkovic M, Pekovic S, Nedeljkovic N.
Department for Neurobiology, Institute for Biological Research "Sinisa Stankovic", University
of Belgrade, Bulevar Despota Stefana 142, 11000 Belgrade, Republic of Serbia.
[email protected]
Abstract
The ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), an enzyme involved in
degradation of extracellular adenosine triphosphate (ATP), is expressed on nerve fibers in
different brain regions, including cortex. Here we studied the expression and role of this enzyme
after unilateral cortical stab injury in rats. In cortical sections of control rats, NTPDase3
immunoreactivity was associated with two types of fibers: thin processes, occasionally with
small mushroom-like protrusions and slightly thicker fibers with more pronounced and more
frequent varicosities, whereas immunopositive neuronal perycaria were never observed.
Although NTPDase3-positive thin processes and thicker fibers, by general appearance, size and
shape, could be dendrites and axons, respectively, they were never immunopositive for
microtubule associated protein-2 or neurofilament H subunit. Cortical stab injury induced rapid
(within 4 hours) focal varicose swelling that evolved over time to prominent beading of
NTPDase3-positive fibers. The NTPDase3-positive fibers in all experimental groups also
abundantly express NTPDase1, ecto-5'-nucleotidase and P2X2 receptor channels. Because the
brain injury causes a massive ATP release, it is reasonable to conclude that purinoreceptors and
ectonucleotidases play an important role in the process of neuritic beading.
Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
PMID: 20620196 [PubMed - in process]
=====================================================================================
J Neurochem. 2010 Mar 14. [Epub ahead of print]
OKEY
Anoxia leads to a rapid translocation of
human trypsinogen 4 to the plasma
membrane of cultured astrocytes.
Tárnok K, Szilágyi L, Berki T, Németh P, Gráf L, Schlett K.
Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, Hungary.
Abstract
J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06685.x Abstract Trypsinogen 4 is specifically
expressed in the human brain, mainly by astroglial cells. Although its exact role in the nervous
tissue is yet unclear, trypsin 4-mediated pathological processes were suggested in Alzheimer's
disease, multiple sclerosis and ischemic injury. In the present study, we analyzed the intracellular
distribution of fluorescently tagged human trypsinogen 4 isoforms during normal and anoxic
conditions in transfected mouse primary astrocytes. Our results show that initiation of anoxic
milieu by the combined action of KCN treatment and glucose deprivation rapidly leads to the
association of leader peptide containing trypsinogen 4 constructs to the plasma membrane. Using
rhodamine 110 bis-(CBZ-L-isoleucyl-L-prolyl-L-arginine amide), a synthetic chromogen peptide
substrate of trypsin, we show that anoxia can promote extracellular activation of trypsinogen 4
indicating that extracellular activation of human trypsinogen 4 can be an important component in
neuropathological changes of the injured human brain.
PMID: 20345763 [PubMed - as supplied by publisher]
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PLoS One. 2010 Jun 30;5(6):e11383.
OKEY
CE8A5C65CC334
/projects/entrez/E
Valproate administered after traumatic brain
injury provides neuroprotection and
improves cognitive function in rats.
Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, Moore AN.
Department of Neurobiology and Anatomy, University of Texas Health Science Center at
Houston, Houston, Texas, United States of America. [email protected]
Abstract
BACKGROUND: Traumatic brain injury (TBI) initiates a complex series of neurochemical and
signaling changes that lead to pathological events including neuronal hyperactivity, excessive
glutamate release, inflammation, increased blood-brain barrier (BBB) permeability and cerebral
edema, altered gene expression, and neuronal dysfunction. It is believed that a drug combination,
or a single drug acting on multiple targets, may be an effective strategy to treat TBI. Valproate, a
widely used antiepileptic drug, has a number of targets including GABA transaminase, voltagegated sodium channels, glycogen synthase kinase (GSK)-3, and histone deacetylases (HDACs),
and therefore may attenuate a number of TBI-associated pathologies.
METHODOLOGY/PRINCIPAL FINDINGS: Using a rodent model of TBI, we tested if postinjury administration of valproate can decrease BBB permeability, reduce neural damage and
improve cognitive outcome. Dose-response studies revealed that systemic administration of 400
mg/kg (i.p.), but not 15, 30, 60 or 100 mg/kg, increases histone H3 and H4 acetylation, and
reduces GSK-3 activity, in the hippocampus. Thirty min post-injury administration of 400 mg/kg
valproate improved BBB integrity as indicated by a reduction in Evans Blue dye extravasation.
Consistent with its dose response to inhibit GSK-3 and HDACs, valproate at 400 mg/kg, but not
100 mg/kg, reduced TBI-associated hippocampal dendritic damage, lessened cortical contusion
volume, and improved motor function and spatial memory. These behavioral improvements were
not observed when SAHA (suberoylanilide hydroxamic acid), a selective HDAC inhibitor, was
administered.
CONCLUSION/SIGNIFICANCE: Our findings indicate that valproate given soon after TBI can
be neuroprotective. As clinically proven interventions that can be used to minimize the damage
following TBI are not currently available, the findings from this report support the further testing
of valproate as an acute therapeutic strategy.
PMID: 20614021 [PubMed - indexed for MEDLINE]PMCID: PMC2894851Free PMC Article
=====================================================================================
J Cereb Blood Flow Metab. 2010 Sep;30(9):1564-76. Epub 2010 Jul 7.
OKEY
MicroRNAs as effectors of brain function
with roles in ischemia and injury,
neuroprotection, and neurodegeneration.
Saugstad JA.
Robert Stone Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
[email protected]
Abstract
MicroRNAs are small RNAs that function as regulators of posttranscriptional gene expression.
MicroRNAs are encoded by genes, and processed to form ribonucleoprotein complexes that bind
to messenger RNA (mRNA) targets to repress translation or degrade mRNA transcripts. The
microRNAs are particularly abundant in the brain where they serve as effectors of neuronal
development and maintenance of the neuronal phenotype. They are also expressed in dendrites
where they regulate spine structure and function as effectors in synaptic plasticity. MicroRNAs
have been evaluated for their roles in brain ischemia, traumatic brain injury, and spinal cord
injury, and in functional recovery after ischemia. They also serve as mediators in the brain's
response to ischemic preconditioning that leads to endogenous neuroprotection. In addition,
microRNAs are implicated in neurodegenerative disorders, including Alzheimer's, Huntington,
Parkinson, and Prion disease. The discovery of microRNAs has expanded the potential for
human diseases to arise from genetic mutations in microRNA genes or sequences within their
target mRNAs. This review discusses microRNA discovery, biogenesis, mechanisms of gene
regulation, their expression and function in the brain, and their roles in brain ischemia and injury,
neuroprotection, and neurodegeneration.
PMID: 20606686 [PubMed - indexed for MEDLINE]PMCID: PMC2932764Free PMC Article
=====================================================================
================Gen Physiol Biophys. 2010 Jun;29(2):113-21.
Effects of one-day reperfusion after transient
forebrain ischemia on circulatory system in
the rat.
Kravcukova P, Danielisova V, Nemethova M, Burda J, Gottlieb M.
Institute of Neurobiology SAS, Soltesovej 4/6, 040 01 Kosice, Slovakia. [email protected]
Abstract
Although ischemia/reperfusion injury remains incompletely understood, it appears that reactive
oxygen species produced mainly during postischemic recirculation play a critical role. The
present study examined the impact of forebrain ischemia and subsequent one-day reperfusion on
several blood parameters. We determined glutamate concentration in whole blood, measured
Cu/Zn- and Mn-SOD (superoxide dismutase) activity in blood cells as well as plasma, and
investigated the prevalence of single and double strand breaks of lymphocyte DNA. The results
of our experiment showed that the concentration of glutamic acid in whole blood was increased
by about 25%. Antioxidant activity of total SOD and Cu/Zn-SOD was reduced in blood cells and
plasma. Mn-SOD activity in blood cells was not affected by ischemic insult and one-day
reperfusion, but we detected its significantly lower activity in samples of plasma. We observed a
weakly reduced level of double and a significantly elevated level of single strand breaks of
lymphocyte DNA. In conclusion, one day of recovery after the ischemic attack failed to return
peripheral circulatory system to physiological conditions. Reduced antioxidant capacity in the
blood and an elevated level of excitotoxic amino acid glutamate may cause lymphocyte DNA
damage, and probably contribute to insufficient postischemic recovery of brain tissue.
PMID: 20577022 [PubMed - indexed for MEDLINE]
=====================================================================
================J Neurotrauma. 2010 Sep;27(9):1635-41.
Intracranial pressure following penetrating
ballistic-like brain injury in rats.
Wei G, Lu XC, Yang X, Tortella FC.
Department of Applied Neurobiology, Walter Reed Army Institute of Research, Silver Spring,
Maryland 20910, USA. [email protected]
Abstract
Penetrating ballistic brain injury involves a leading shockwave producing a temporary cavity
causing substantial secondary injury. In response to the prevalence of this type of brain trauma in
the military, a rat model of penetrating ballistic-like brain injury (PBBI) was established. This
study focuses on cerebral physiological responses resulting from a PBBI, specifically the
immediate and delayed changes in intracranial pressure (ICP) and cerebral perfusion pressure
(CPP). ICP/CPP was measured continuously in rats subjected to PBBI, probe insertion alone, or
sham injury. Immediately following the PBBI, a transient (<0.1 sec) and dramatic elevation of
ICP reaching 280.0 ± 86.0 mm Hg occurred, accompanied by a profound decrease in CPP to 180.2 ± 90.1 mm Hg. This emergent ICP/CPP response resolved spontaneously within seconds,
but was followed by a slowly-developing and sustained secondary phase, which peaked at 24 h
post-injury, reaching 37.2 ± 10.4 mm Hg, and remained elevated until 72 h post-injury. The
measured decrease in CPP reached 85.3 ± 17.2 mm Hg at 3 h post-injury. By comparison, probe
insertion alone did not produce the immediate ICP crisis (28.6 ± 9.1 mm Hg), and only a mild and
sustained increase in ICP (13.5 ± 2.1 mm Hg) was observed in the following 3 h post-injury.
Injury severity, as measured by lesion volume, brain swelling, and neurological deficits at 1, 3,
and 7 days post-injury, also reflected the distinctive differences between the dynamics of the
PBBI versus controls. These results not only reinforced the severe nature of this model in
mimicking the ballistic effect of PBBI, but also established cerebral pathophysiological targets
for neuroprotective therapies.
PMID: 20568960 [PubMed - in process]
=====================================================================
================J Neurotrauma. 2010 Jun;27(6):1081-9.
OKEY
Injury severity differentially alters sensitivity
to dexamethasone after traumatic brain
injury.
Taylor AN, Rahman SU, Tio DL, Gardner SM, Kim CJ, Sutton RL.
Department of Neurobiology, Brain Research Institute and Brain Injury Research Center, David
Geffen School of Medicine at UCLA, and West Los Angeles Healthcare Center, VA Greater Los
Angeles Healthcare System (VAGLAHS), Los Angeles, California 90095-1763, USA.
[email protected]
Abstract
We have reported differential short- and long-term dysregulation of the neuroendocrine stress
response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We
have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects
on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity
of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal
loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus.
TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two
different impact velocities and compression depths, to produce either moderate or mild CCI. At 7
and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog
dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30
min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed
corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both
days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the
moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH
(1.0 and 10.0 microg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury
condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced
sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered
pituitary responses to CRH, contribute to the short- and long-term attenuation of the
neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in
glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity
requires further investigation.
PMID: 20560754 [PubMed - indexed for MEDLINE]
=====================================================================================
Histochem Cell Biol. 2010 Aug;134(2):159-69. Epub 2010 Jun 18.
OKEY
Brain injury induces cholesterol 24hydroxylase (Cyp46) expression in glial cells
in a time-dependent manner.
Smiljanic K, Lavrnja I, Mladenovic Djordjevic A, Ruzdijic S, Stojiljkovic M, Pekovic S, Kanazir
S.
Department of Neurobiology, Institute for Biological Research Sinisa Stankovic, University of
Belgrade, Belgrade, Serbia.
Abstract
Maintaining the cholesterol homeostasis is essential for normal CNS functioning. The enzyme
responsible for elimination of cholesterol excess from the brain is cholesterol 24-hydroxylase
(Cyp46). Since cholesterol homeostasis is disrupted following brain injury, in this study we
examined the effect of right sensorimotor cortex suction ablation on cellular and temporal pattern
of Cyp46 expression in the rat brain. Increased expression of Cyp46 at the lesion site at all post
injury time points (2, 7, 14, 28 and 45 days post injury, dpi) was detected. Double
immunofluorescence staining revealed colocalization of Cyp46 expression with different types of
glial cells in time-dependent manner. In ED1(+) microglia/macrophages Cyp46 expression was
most prominent at 2 and 7 dpi, whereas Cyp46 immunoreactivity persisted in reactive astrocytes
throughout all time points post-injury. However, during the first 2 weeks Cyp46 expression was
enhanced in both GFAP(+) and Vim(+) astrocytes, while at 28 and 45 dpi its expression was
mostly associated with GFAP(+) cells. Pattern of neuronal Cyp46 expression remained
unchanged after the lesion, i.e. Cyp46 immunostaining was detected in dendrites and cell body,
but not in axons. The results of this study clearly demonstrate that in pathological conditions,
like brain injury, Cyp46 displayed atypical expression, being expressed not only in neuronal
cells, but also in microglia and astrocytes. Therefore, injury-induced expression of Cyp46 in
microglial and astroglial cells may be involved in the post-injury removal of damaged cell
membranes contributing to re-establishment of the brain cholesterol homeostasis.
PMID: 20559650 [PubMed - in process]
=====================================================================================
Brain Pathol. 2010 Nov;20(6):1055-68. doi: 10.1111/j.1750-3639.2010.00412.x. Epub 2010 Jun
15.
OKEY
Proteolysis of submembrane cytoskeletal
proteins ankyrin-G and αII-spectrin
following diffuse brain injury: a role in white
matter vulnerability at Nodes of Ranvier.
Reeves TM, Greer JE, Vanderveer AS, Phillips LL.
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth
University Medical Center, Richmond, VA, USA. [email protected]
Abstract
A high membrane-to-cytoplasm ratio makes axons particularly vulnerable to traumatic injury.
Posttraumatic shifts in ionic homeostasis promote spectrin cleavage, disrupt ankyrin linkages and
destabilize axolemmal proteins. This study contrasted ankyrin-G and αII-spectrin degradation in
cortex and corpus callosum following diffuse axonal injury produced by fluid percussion insult.
Ankyrin-G lysis occurred preferentially in white matter, with acute elevation of all fragments and
long-term reduction of a low kD form. Calpain-generated αII-spectrin fragments increased in
both regions. Caspase-3 lysis of αII-spectrin showed a small, acute rise in cortex but was absent
in callosum. White matter displayed nodal damage, with horseradish peroxidase permeability
into the submyelin space. Ankyrin-G-binding protein neurofascin and spectrin-binding protein
ankyrin-B showed acute alterations in expression. These results support ankyrin-G vulnerability
in white matter following trauma and suggest that ankyrin-G and αII-spectrin proteolysis disrupts
Node of Ranvier integrity. The time course of such changes were comparable to previously
observed functional deficits in callosal fibers.
© 2010 The Authors; Brain Pathology © 2010 International Society of Neuropathology.
PMID: 20557305 [PubMed - in process]
=====================================================================================
Nat Rev Neurol. 2010 Jul;6(7):393-403. Epub 2010 Jun 15.
OKEY
Blood-brain barrier breakdown as a
therapeutic target in traumatic brain injury.
Shlosberg D, Benifla M, Kaufer D, Friedman A; Medscape.
Department of Physiology and Neurobiology, Zlotowski Center for Neuroscience, Ben-Gurion
University of the Negev, Beer-Sheva 84105, Israel.
Abstract
Traumatic brain injury (TBI) is the leading cause of death in young adults and children. The
treatment of TBI in the acute phase has improved substantially; however, the prevention and
management of long-term complications remain a challenge. Blood-brain barrier (BBB)
breakdown has often been documented in patients with TBI, but the role of such vascular
pathology in neurological dysfunction has only recently been explored. Animal studies have
demonstrated that BBB breakdown is involved in the initiation of transcriptional changes in the
neurovascular network that ultimately lead to delayed neuronal dysfunction and degeneration.
Brain imaging data have confirmed the high incidence of BBB breakdown in patients with TBI
and suggest that such pathology could be used as a biomarker in the clinic and in drug trials.
Here, we review the neurological consequences of TBI, focusing on the long-term complications
of such injuries. We present the clinical evidence for involvement of BBB breakdown in TBI and
examine the primary and secondary mechanisms that underlie such pathology. We go on to
consider the consequences of BBB injury, before analyzing potential mechanisms linking
vascular pathology to neuronal dysfunction and degeneration, and exploring possible targets for
treatment. Finally, we highlight areas for future basic research and clinical studies into TBI.
PMID: 20551947 [PubMed - in process]
=====================================================================================
J Physiol. 2010 Aug 1;588(Pt 15):2823-38. Epub 2010 Jun 14.
OKEY
Development of calcium-permeable AMPA
receptors and their correlation with NMDA
receptors in fast-spiking interneurons of rat
prefrontal cortex.
Wang HX, Gao WJ.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen
Lane, Philadelphia, PA 19129, USA.
Abstract
Abnormal influx of Ca(2+) is thought to contribute to the neuronal injury associated with a
number of brain disorders, and Ca(2+)-permeable AMPA receptors (CP-AMPARs) play a
critical role in the pathological process. Despite the apparent vulnerability of fast-spiking (FS)
interneurons in neurological disorders, little is known about the CP-AMPARs expressed by
functionally identified FS interneurons in the developing prefrontal cortex (PFC). We
investigated the development of inwardly rectifying AMPA receptor-mediated currents and their
correlation with NMDA receptor-mediated currents in FS interneurons in the rat PFC. We found
that 78% of the FS interneurons expressed a low rectification index, presumably Ca(2+)permeable AMPARs, with only 22% exhibiting AMPARs with a high rectification index,
probably Ca(2+) impermeable (CI). FS interneurons with CP-AMPARs exhibited properties
distinct from those expressing CI-AMPARs, although both displayed similar morphologies,
passive membrane properties and AMPA currents at resting membrane potentials. The AMPA
receptors also exhibited dramatic changes during cortical development with significantly more
FS interneurons with CP-AMPARs and a clearly decreased rectification index during
adolescence. In addition, FS interneurons with CP-AMPARs exhibited few or no NMDA
currents, distinct frequenc
=====================================================================
================J Neurosci Res. 2010 Oct;88(13):2899-910.
Involvement of nerve injury and activation of
peripheral glial cells in tetanic sciatic
stimulation-induced persistent pain in rats.
Liang L, Wang Z, Lü N, Yang J, Zhang Y, Zhao Z.
Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical
Neurobiology, Fudan University, Shanghai, China.
Abstract
Tetanic stimulation of the sciatic nerve (TSS) produces long-lasting pain hypersensitivity in rats.
Long-term potentiation (LTP) of C- and A-fiber-evoked field potentials in the spinal cord has
been explored as contributing to central sensitization in pain pathways. However, the peripheral
mechanism underlying TSS-induced pain hypersensitivity remains largely unknown. We
investigated the effect of TSS on peripheral nerve and the expression of activating transcription
factor 3 (ATF3) in dorsal root ganglion (DRG) as a marker of neuronal injury. TSS induced a
mechanical allodynia for at least 35 days and induced ATF3 expression in the ipsilateral DRG.
ATF3 is colocalized with NF200-labeled myelinated DRG neurons or CGRP- and IB4-labeled
unmyelinated ones. Furthermore, we found that TSS induced Wallerian degeneration of sciatic
nerve at the level of myelinisation by S100 protein (to label Schwann cells)
immunohistochemistry, luxol fast blue staining, and electron microscopy. TSS also elicited the
activation of satellite glial cells (SGCs) and enhanced the colocalization of GFAP and P2X7
receptors. Repeated local treatment with tetrodotoxin decreased GFAP expression in SGCs and
behavioral allodynia induced by TSS. Furthermore, reactive microglia and astrocytes were found
in the spinal dorsal horn after TSS. These results suggest that TSS-induced nerve injury and glial
activation in the DRG and spinal dorsal horn may be involved in cellular mechanisms underlying
the development of persistent pain after TSS and that TSS-induced nerve injury may be used as a
novel neuropathic pain model.
(c) 2010 Wiley-Liss, Inc.
PMID: 20544834 [PubMed - in process]
=====================================================================
================Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11104-9. Epub 2010 Jun
1.
OKEY
Long-lasting reduction in hippocampal
neurogenesis by alcohol consumption in
adolescent nonhuman primates.
Taffe MA, Kotzebue RW, Crean RD, Crawford EF, Edwards S, Mandyam CD.
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La
Jolla, CA 92037, USA.
Abstract
Binge alcohol consumption in adolescents is increasing, and studies in animal models show that
adolescence is a period of high vulnerability to brain insults. The purpose of the present study
was to determine the deleterious effects of binge alcohol on hippocampal neurogenesis in
adolescent nonhuman primates. Heavy binge alcohol consumption over 11 mo dramatically and
persistently decreased hippocampal proliferation and neurogenesis. Combinatorial analysis
revealed distinct, actively dividing hippocampal neural progenitor cell types in the subgranular
zone of the dentate gyrus that were in transition from stem-like radial glia-like cells (type 1) to
immature transiently amplifying neuroblasts (type 2a, type 2b, and type 3), suggesting the
evolutionary conservation of milestones of neuronal development in macaque monkeys. Alcohol
significantly decreased the number of actively dividing type 1, 2a, and 2b cell types without
significantly altering the early neuronal type 3 cells, suggesting that alcohol interferes with the
division and migration of hippocampal preneuronal progenitors. Furthermore, the lasting
alcohol-induced reduction in hippocampal neurogenesis paralleled an increase in neural
degeneration mediated by nonapoptotic pathways. Altogether, these results demonstrate that the
hippocampal neurogenic niche during adolescence is highly vulnerable to alcohol and that
alcohol decreases neuronal turnover in adolescent nonhuman primate hippocampus by altering
the ongoing process of neuronal development. This lasting effect, observed 2 mo after alcohol
discontinuation, may underlie the deficits in hippocampus-associated cognitive tasks that are
observed in alcoholics.
PMID: 20534463 [PubMed - indexed for MEDLINE]PMCID: PMC2890755 [Available on
2010/12/15]
=====================================================================
================J Med Food. 2010 Jun;13(3):557-63.
OKEY
Zizyphus attenuates ischemic damage in the
gerbil hippocampus via its antioxidant effect.
Yoo KY, Li H, Hwang IK, Choi JH, Lee CH, Kwon DY, Ryu SY, Kim YS, Kang IJ, Shin HC,
Won MH.
Department of Anatomy and Neurobiology, Institute of Neurodegeneration and
Neuroregeneration, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Abstract
The fruit of Zizyphus jujuba has been used as a traditional Chinese medicinal herb and
considered for thousands of years to affect various physiological functions in the body. We
obtained a Z. jujuba extract (ZJE) and observed the neuroprotective effects of ZJE against
ischemic damage in gerbils that had received repeated oral administrations of ZJE for 10 days. In
the ZJE-treated ischemia group, neuronal nuclei (a marker for neurons)-immunoreactive neurons
were abundant (58.4% vs. sham group) in the hippocampal CA1 region 4 days after
ischemia/reperfusion compared to those in the vehicle-treated ischemia group (11.3%). In
addition, ZJE treatment significantly decreased the reactive gliosis of astrocytes and microglia in
the CA1 region compared to that in the vehicle-treated group 4 days after ischemia/reperfusion.
Immunoreactivities of Cu,Zn-superoxide dismutase (SOD1) and brain-derived neurotrophic
factor in the ZJE-treated ischemia group were higher those in the vehicle-treated ischemia group
4 days after ischemia/reperfusion. In addition, in the ZJE-treated ischemia group, levels of
hydroxynonenal, an indicator of lipid peroxidation, were much lower than those in the vehicletreated ischemia group after ischemia/reperfusion. These results suggest that the repeated
supplements of ZJE can protect neurons from ischemic damage via up-regulation of SOD1 and
reduction of lipid peroxidation in the ischemic hippocampal CA1 region.
PMID: 20521981 [PubMed - indexed for MEDLINE]
=====================================================================================
J Neurotrauma. 2010 Aug;27(8):1439-48.
High blood glucose does not adversely affect
outcome in moderately brain-injured
rodents.
Hill J, Zhao J, Dash PK.
Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston,
Texas 77225, USA.
Abstract
In a number of clinical studies researchers have reported that acute hyperglycemia is associated
with increased mortality and worsened neurological outcome in patients with traumatic brain
injury (TBI). In contrast, it has been demonstrated that intensive insulin therapy to lower blood
glucose can lead to an increased frequency of hypoglycemic episodes and poor outcome.
Consistent with this, experimental and clinical studies have shown that TBI causes a "metabolic
crisis" in the injured brain, suggesting that a reduction in glucose availability may exacerbate
brain damage. We therefore examined the consequences of hyperglycemia on cognitive and
pathological measures. Using a rodent model of TBI, we find that when acute hyperglycemia is
induced in animals prior to injury, there is little to no change in motor and cognitive
performance, contusion volume, or cerebral edema. To examine the consequences of persistent
hyperglycemia (as seen in diabetic patients), animals were treated with streptozotocin (STZ) to
induce type 1 diabetes. We find that the presence of persistent STZ-induced hyperglycemia
results in a reduction of brain edema. Insulin therapy to reduce blood glucose reverses this
beneficial effect of hyperglycemia. Taken together, our results indicate that an acute increase in
blood glucose levels may not be harmful, and that intervention with insulin therapy to lower
blood glucose levels in TBI patients may increase secondary brain damage.
PMID: 20504157 [PubMed - in process]
=====================================================================================
J Cereb Blood Flow Metab. 2010 May 19. [Epub ahead of print]
Magnetic resonance imaging of regional
hemodynamic and cerebrovascular recovery
after lateral fluid-percussion brain injury in
rats.
Hayward NM, Tuunanen PI, Immonen R, Ndode-Ekane XE, Pitkänen A, Gröhn O.
Biomedical Imaging Unit, Department of Neurobiology, A. I. Virtanen Institute for Molecular
Sciences, University of Eastern Finland, Kuopio, Finland.
Abstract
Hemodynamic and cerebrovascular factors are crucially involved in secondary damage after
traumatic brain injury (TBI). With magnetic resonance imaging, this study aimed to quantify
regional cerebral blood flow (CBF) by arterial spin labeling and cerebral blood volume by using
an intravascular contrast agent, during 14 days after lateral fluid-percussion injury (LFPI) in rats.
Immunohistochemical analysis of vessel density was used to evaluate the contribution of
vascular damage. Results show widespread ipsilateral and contralateral hypoperfusion, including
both the cortex and the hippocampus bilaterally, as well as the ipsilateral thalamus.
Hemodynamic unrest may partly be explained by an increase in blood vessel density over a
period of 2 weeks in the ipsilateral hippocampus and perilesional cortex. Furthermore, three
phases of perilesional alterations in CBF, progressing from hypoperfusion to normal and back to
hypoperfusion within 2 weeks were shown for the first time in a rat TBI model. These three
phases were similar to hemodynamic fluctuations reported in TBI patients. This makes it feasible
to use LFPI in rats to study mechanisms behind hemodynamic changes and to explore novel
therapeutic approaches for secondary brain damage after TBI.Journal of Cerebral Blood Flow &
Metabolism advance online publication, 19 May 2010; doi:10.1038/jcbfm.2010.67.
PMID: 20485295 [PubMed - as supplied by publisher]
=====================================================================================
Nat Rev Neurol. 2010 Jun;6(6):328-36. Epub 2010 May 18.
OKEY
Neurobiology of injury to the developing
brain.
Deng W.
Department of Cell Biology and Human Anatomy, Institute for Pediatric Regenerative Medicine,
School of Medicine, University of California Davis, 2425 Stockton Boulevard, Sacramento, CA
95817, USA. [email protected]
Abstract
Owing to improved survival rates of premature newborns, the number of very low birth weight
infants is rising. Preterm infants display a greater propensity for brain injury caused by hypoxic
or ischemic events, infection and/or inflammation that results in prominent white matter injury
(WMI) than infants carried to full term. The intrinsic vulnerability of developing oligodendroglia
to excitotoxic, oxidative and inflammatory forms of injury is a major factor in the pathogenesis
of this condition. Furthermore, activated microglia and astrogliosis are critically involved in
triggering WMI. Currently, no specific treatment is available for this kind of injury. Injury to the
premature brain can substantially influence brain development and lead to disability. Impairment
of the main motor pathways, such as the corticospinal tract, in the perinatal period contributes
substantially to clinical outcome. Advanced neuroimaging techniques have led to greater
understanding of the nature of both white and gray matter injury in preterm infants. Further
research is warranted to examine the translational potential of preclinical therapeutic strategies
for controlling such injury and preserving the integrity of motor pathways in preterm infants.
PMID: 20479779 [PubMed - indexed for MEDLINE]
=====================================================================================
Brain Res. 2010 Jul 23;1345:197-205. Epub 2010 May 15.
OKEY
Dynamic change of hydrogen sulfide during
global cerebral ischemia-reperfusion and its
effect in rats.
Ren C, Du A, Li D, Sui J, Mayhan WG, Zhao H.
Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, Henan,
PR China.
Abstract
Hydrogen sulfide (H(2)S) is a gaseous messenger and serves as an important neuromodulator in
central nervous system. In the current study, we investigated the change of H(2)S and
cystathionine beta-synthase (CBS), an H(2)S-synthesizing enzyme at different time points of
reperfusion following global cerebral ischemia in rats, and the effect of exogenous H(2)S on
global cerebral ischemia-reperfusion injury. First, we used global cerebral ischemia-reperfusion
model by occlusion of bilateral common carotid arteries and vertebral arteries. Next, we
measured H(2)S levels in the hippocampus, cortex and plasma, the activity of H(2)Ssynthesizing enzymes and expression of CBS mRNA and protein in the hippocampus and cortex
at 12 h, 24 h, 48 h, 72 h and 7 days of reperfusion following 15 min cerebral ischemia. Second,
we pretreated rats with different doses of sodium hydrogen sulfide (NaHS), an H(2)S donor and
observed its effect on neuronal injury induced by 7 days of reperfusion after 15 min global
cerebral ischemia. We found that when compared to sham group the amount of H(2)S in the
hippocampus was increased significantly at 12 h of reperfusion after cerebral ischemia, markedly
decreased at 24 h, restored to the same level as that in sham group at 48 h and maintained at 72 h
and 7 days. The same change tendency in the levels of H(2)S was found in the cortex as
described for the hippocampus. We found a similar change tendency in the activity of H(2)Ssynthesizing enzymes, CBS mRNA and protein expression to that in the H(2)S level at different
time points of reperfusion. Furthermore, while 180 micromol/kg NaHS pretreatment deteriorated
the neuronal injury after global cerebral ischemia, 25 micromol/kg NaHS attenuated the neuronal
injury. We suggest that a decrease of H(2)S level at 24 h of reperfusion after global cerebral
ischemia may be involved in neuronal injury after cerebral ischemia and lower concentration
rather than higher concentration of exogenous H(2)S may offer a protection against the neuronal
injury induced by global cerebral ischemia-reperfusion.
Copyright 2010 Elsevier B.V. All rights reserved.
PMID: 20478278 [PubMed - indexed for MEDLINE]
=====================================================================
================Am J Pathol. 2010 Jul;177(1):300-10. Epub 2010 May 14.
OKEY
Oligemic hypoperfusion differentially affects
tau and amyloid-{beta}.
Koike MA, Green KN, Blurton-Jones M, Laferla FM.
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological
Disorders, University of California, Irvine, 3212 Biological Sciences III, Irvine, CA 92697-4545,
USA.
Abstract
Decreased blood flow to the brain in humans is associated with altered Alzheimer's disease
(AD)-related pathology, although the underlying mechanisms by which hypoperfusion influences
AD neuropathology remains unknown. To try to address this question, we developed an oligemic
model of cerebral hypoperfusion in the 3xTg-AD mouse model of AD. We bilaterally and
transiently occluded the common carotid artery and then examined the molecular and cellular
pathways by which hypoperfusion influenced tau and amyloid-beta proteins. We report the novel
finding that a single, mild, transient hypoperfusion insult acutely increases Abeta levels by
enhancing beta-secretase protein expression. In contrast, transient hypoperfusion markedly
decreases total tau levels, coincident with activation of macroautophagy and ubiquitinproteosome pathways. Furthermore, we find that oligemia results in a significant increase
specifically in tau phosphorylated at serine(212) and threonine(214), a tau epitope associated
with paired helical filaments in AD patients. Despite the mild and transient nature of this
hypoperfusion injury, the pattern of decreased total tau, altered phosphorylated tau, and
increased amyloid-beta persisted for several weeks postoligemia. Our study indicates that a
single, mild, cerebral hypoperfusion event produces profound and long lasting effects on both tau
and amyloid-beta. This finding may have implications for the pathogenesis of AD, as it indicates
for the first time that total tau and amyloid-beta are differentially impacted by mild
hypoperfusion.
PMID: 20472896 [PubMed - in process]PMCID: PMC2893673 [Available on 2011/7/1]
Publication Types, Grant Support
=====================================================================
================Exp Brain Res. 2010 Jun;203(4):693-700. Epub 2010 May 12.
OKEY
Recovery of function following unilateral
damage to visuoparietal cortex.
Rushmore RJ, Payne B, Valero-Cabre A.
Laboratory for Cerebral Dynamics, Plasticity and Rehabilitation, Department of Anatomy and
Neurobiology, Boston University School of Medicine, 700 Albany Street, W702, Boston, MA
02118, USA. [email protected]
Abstract
Damage to the visuoparietal cortex located in the banks of the middle suprasylvian gyrus of the
cat has been shown to produce a deficit in the detection and localization of moving visual cues
presented in the contralesional visual hemifield. There is evidence from reversible cooling
deactivation studies that the integrity of this orienting function is not completely dependent on
the VP cortex and that under the right circumstances, other brain regions may come online and
completely take over the processing that subserves this behavior. We examined the recovery of
orienting behavior after unilateral damage to the VP cortex. We found that consistent with
previous data, VP damage produced an impairment in the capacity to detect and orient to moving
visual stimuli in the contralesional visual field. Over a span of days, spontaneous recovery fully
occurred. The ability to detect and localize static visual stimuli was tested as a fiducial measure
of parietal cortex function, and this function did not recover. We conclude that the detection and
localization of moving visual stimuli is not a function that requires VP cortex and argue for the
existence of a parallel and redundant subcortical-cortical brain network that serves as the
substrate for recovery of function.
PMID: 20461362 [PubMed - indexed for MEDLINE]
=====================================================================
================J Neuroimmunol. 2010 Jun;223(1-2):77-83. Epub 2010 May 10.
OKEY
Beta-adrenoceptor mediated surgery-induced
production of pro-inflammatory cytokines in
rat microglia cells.
Wang J, Li J, Sheng X, Zhao H, Cao XD, Wang YQ, Wu GC.
Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical
Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
[email protected]
Abstract
Immunological changes initiated by major operative injury may result in inflammatory responses
in both peripheral and central nervous system, which may lead to organ dysfunction. Recent
studies indicate that beta-adrenergic receptors (beta-ARs) may mediate production of proinflammatory cytokines in the brain. In the present study propranolol (beta-AR antagonist), but
not prazosin (alpha1-AR antagonist), antagonized surgical trauma induced pro-inflammatory
cytokine production in microglia cells isolated from rats. beta-AR activation in the absence of
pro-inflammatory stimuli increased IL-1beta, TNF-alpha and IL-6 mRNA and protein
expressions in the primary microglia cell culture. Isoproterenol (beta-AR agonist) treatment
induced a time- and concentration-dependent increase of IL-1beta in cells. Both ERK1/2 and P38
MAPK inhibitor, but not PKA and JNK1/2 inhibitor abrogated isoproterenol-induced IL-1beta
and IL-6 production in microglia cells. In conclusion, the results suggest that beta-ARs possess
pro-inflammatory properties by modulating the functions of microglia cell.
Copyright 2010 Elsevier B.V. All rights reserved.
PMID: 20452680 [PubMed - indexed for MEDLINE]
=====================================================================================
Exp Neurol. 2010 Sep;225(1):60-73. Epub 2010 May 5.
OKEY
Analysis of combinatorial variability reveals
selective accumulation of the fibronectin type
III domains B and D of tenascin-C in injured
brain.
Dobbertin A, Czvitkovich S, Theocharidis U, Garwood J, Andrews MR, Properzi F, Lin R,
Fawcett JW, Faissner A.
Department of Cell Morphology and Molecular Neurobiology, Ruhr University of Bochum,
44780 Bochum, Germany.
Abstract
Tenascin-C (Tnc) is a multimodular extracellular matrix glycoprotein that is markedly
upregulated in CNS injuries where it is primarily secreted by reactive astrocytes. Different Tnc
isoforms can be generated by the insertion of variable combinations of one to seven (in rats)
alternatively spliced distinct fibronectin type III (FnIII) domains to the smallest variant. Each
spliced FnIII repeat mediates specific actions on neurite outgrowth, neuron migration or
adhesion. Hence, different Tnc isoforms might differentially influence CNS repair. We explored
the expression pattern of Tnc variants after cortical lesions and after treatment of astrocytes with
various cytokines. Using RT-PCR, we observed a strong upregulation of Tnc transcripts
containing the spliced FnIII domains B or D in injured tissue at 2-4 days post-lesion (dpl).
Looking at specific combinations, we showed a dramatic increase of Tnc isoforms harboring the
neurite outgrowth-promoting BD repeat with both the B and D domains being adjacent to each
other. Isoforms containing only the axon growth-stimulating spliced domain D were also
dramatically enhanced after injury. Injury-induced increase of Tnc proteins comprising the
domain D was confirmed by Western Blotting and immunostaining of cortical lesions. In
contrast, the FnIII modules C and AD1 were weakly modulated after injury. The growth cone
repulsive A1A2A4 domains were poorly expressed in normal and injured tissue but the smallest
isoform, which is also repellant, was highly expressed after injury. Expression of the shortest
Tnc isoform and of variants containing B, D or BD, was strongly upregulated in cultured
astrocytes after TGFbeta1 treatment, suggesting that TGFbeta1 could mediate, at least in part, the
injury-induced upregulation of these isoforms. We identified complex injury-induced differential
regulations of Tnc isoforms that may well influence axonal regeneration and repair processes in
the damaged CNS.
Copyright 2010. Published by Elsevier Inc.
PMID: 20451518 [PubMed - indexed for MEDLINE]
=====================================================================================
Auton Neurosci. 2010 Oct 28;157(1-2):9-17. Epub 2010 May 7.
Neurotrophins and acupuncture.
Manni L, Albanesi M, Guaragna M, Barbaro Paparo S, Aloe L.
Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy. [email protected]
Abstract
The aim of this review is to report recent findings and ongoing studies on the effects of
acupuncture on endogenous biological mediators, in particular on neurotrophins such as nerve
growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Acupuncture is a
therapeutic technique and is a part of Traditional Chinese Medicine (TCM). Western descriptions
of the clinical efficacy of acupuncture on pain, inflammation, motor dysfunction, mood
disorders, and seizures are based on the stimulation of several classes of sensory afferent fibers
and the consequent activation of physiological processes similar to those resulting from physical
exercise or deep massage. The established research on the neuro-physiological correlates of
acupuncture has pointed towards endogenous opioids as the principal biological mediators of the
therapeutic actions of this ancient technique. More recently, several classes of molecules, such as
neurotransmitters, cytokines and growth factors, have also been identified as possible mediators
for specific acupuncture effects. This review will focus on the links between acupuncture and a
class of growth factors known as neurotrophins (NTs), which are the main mediators of neural
activity, plasticity and repair following neurodegeneration and/or traumatic injury. A special
emphasis will be placed on the work of our laboratory investigating the role of nerve growth
factor (NGF), the prototypical member of the neurotrophin family, as a mediator of acupuncture
effects in the central nervous system (CNS) and as a modulator of sensory and autonomic
activity.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20451467 [PubMed - in process]
=====================================================================================
Neurol Res. 2010 Nov;32(9):963-70. Epub 2010 May 4.
OKEY
Effects of green tea polyphenols on caveolin-1
of microvessel fragments in rats with
cerebral ischemia.
Zhang S, Liu Y, Zhao Z, Xue Y.
Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang
China.
Abstract
OBJECTIVE: This study was designed to investigate the effects of green tea polyphenols (GTPs)
on the permeability of blood-brain barrier (BBB), and the expression of caveolin-1 and
extracellular signal-regulated kinase ½ (ERK1/2) after cerebral ischemia.
METHODS: Cerebral ischemia was established by middle cerebral artery occlusion (MCAO).
Rats were randomly divided into control and GTP groups, and both included four time points of
interest: MCA occluded for 0 hour, 1 hour, 2 hours, and 4 hours groups. After ischemia,
triphenyltetrazolium chloride staining and Longa's score were used to determine the infarct
volume and neurological deficit. Evans blue (EB) content in the brain tissue was measured to
observe the BBB permeability. RT-PCR, immunohistochemistry, and western blot assessment
were used to detect expression of caveolin-1 in microvessel fragments of cerebral ischemic
tissue. Western blot was also used to examine ERK1/2.
RESULTS: GTPs significantly reduced infarct volume, ameliorated the neurological deficit, and
reduced the permeability of BBB. GTPs also obviously reduced the levels of caveolin-1 mRNA
and protein expression as well as the expression of phosphorylated ERK1/2 in microvessel
fragments of cerebral ischemic tissue, which were enhanced by cerebral ischemia.
DISCUSSION: These data were the first to show that GTPs can decrease the elevated BBB
permeability in the ischemic region, and the protective effects for cerebral injury may be related
to the reduced expression of caveolin-1 and phosphorylated ERK1/2.
PMID: 20444327 [PubMed - in process]
=====================================================================================
Epilepsy Res. 2010 Jun;90(1-2):47-59.
OKEY
Association of the severity of cortical damage
with the occurrence of spontaneous seizures
and hyperexcitability in an animal model of
posttraumatic epilepsy.
Kharatishvili I, Pitkänen A.
Epilepsy Research Laboratory, Department of Neurobiology, A.I. Virtanen Institute for
Molecular Sciences, University of Eastern Finland, and Department of Neurology, Kuopio
University Hospital, FIN-70211 Kuopio, Finland.
Abstract
Posttraumatic epilepsy is a common consequence of traumatic brain injury in humans. Major
predictors for the development of posttraumatic epilepsy include the severity of injury and
occurrence of cortical contusions. The effect of the size or location of the cortical lesion on the
risk of epileptogenesis, however, is poorly understood. Here, we investigated the extent and
location of cortical damage and its association with a lowered seizure threshold and the
occurrence of spontaneous seizures in rats (n=77) that had experienced moderate or severe lateral
fluid-percussion brain injury (FPBI) 12 months earlier. Spontaneous seizures were detected with
video-electroencephalography monitoring and a lowered seizure threshold was determined based
on a pentylenetetrazol (PTZ) test. Cortical atrophy was evaluated from thionin-stained sections
using the Cavalieri estimation in four different experiments in which rats developed either
spontaneous recurrent seizures (i.e., epilepsy) or a lowered seizure threshold. Our data show that
damage to the cortex ipsilateral to the injury was more severe and extended more caudally in
epileptic animals than in those without epilepsy (p<0.05 and p<0.001 for 2 independent
experiments). Further, the extent of the cortical damage correlated positively with chronically
increased hyperexcitability (number of spikes in PTZ test) in animals with traumatic brain injury
(r=-0.54, p<0.05; r=-0.72, p<0.01 for 2 independent experiments). Specifically, cortical lesions
located at the level of the perirhinal, entorhinal, and postrhinal cortices were associated with a
lowered seizure threshold and seizures. The severity of the cortical injury did not correlate with
the severity of hippocampal damage. These findings indicate that, like in humans, the severity of
cortical injury correlates with epileptogenesis and epilepsy in an experimental model of
posttraumatic epilepsy.
Copyright (c) 2010 Elsevier B.V. All rights reserved.
PMID: 20435440 [PubMed - indexed for MEDLINE]
=====================================================================
================Arch Ital Biol. 2010 Mar;148(1):23-32.
OKEY
Ischemic postconditioning in the rat
hippocampus: mapping of proteins involved
in reversal of delayed neuronal death.
Nemethova M, Danielisova V, Gottlieb M, Kravcukova P, Burda J.
Institute of Neurobiology, Slovak Academy of Sciences, Kosice, Slovakia. [email protected]
Abstract
In this study, transient forebrain ischemia was induced in male Wistar rats with subsequent 3
days of reperfusion (ischemia/reperfusion group) or 2 days of reperfusion followed by 5 min
ischemia and another 1 day of reperfusion (postconditioning group) to assess an effect of delayed
postconditioning applied two days after a previous lethal ischemic attack. We have examined
immunoreactivity of antioxidant enzymes (MnSOD, CuZnSOD) and proteins related to apoptosis
development (Bcl-2, Bax). Results of microdensitometric measurements from the vulnerable
hippocampal CA1 region and relatively resistant dentate gyrus were compared to sham controls
and identically, results of postconditioning group were compared to ischemic one. Our findings
show protective effects of postconditioning in both brain regions examined, include increased
expression of antioxidant enzymes, mainly CuZnSOD, what can be demonstrated by
microdensitometric results: CuZnSOD density after ischemia and reperfusion was 6261.5 +/411.35; after postconditioning 9746.6 +/- 584.55. In addition, postconditioning prevents an
excessive ischemia-induced increase of pro-apoptotic protein Bax (Bax density after ischemia
and reperfusion was 3462.51 +/- 321.66; after postconditioning 1766.89 +/- 255.63).
PMID: 20426251 [PubMed - indexed for MEDLINE]
=====================================================================
================Curr Neurol Neurosci Rep. 2010 Jan;10(1):47-52.
Neural injury in sleep apnea.
Lim DC, Veasey SC.
Center for Sleep and Neurobiology, University of Pennsylvania School of Medicine,
Translational Research Building, Room 2115, 125 South 31st Street, Philadelphia, PA, 19104,
USA.
Abstract
Sleepiness has long been recognized as a presenting symptom in obstructive sleep apnea
syndrome, but persistent neurocognitive injury from sleep apnea has been appreciated only
recently. Although therapy for sleep apnea markedly improves daytime symptoms, cognitive
impairments may persist despite long-term therapy with continuous positive airway pressure. We
know now that certain groups of neurons, typically those that are more metabolically active, are
more vulnerable to injury than others. Animal models of sleep apnea oxygenation patterns have
been instrumental in elucidating mechanisms of injury. The hypoxia/reoxygenation events result
in oxidative, inflammatory, and endoplasmic reticulum stress responses in susceptible neural
groups. With molecular pathways being fleshed out in animal models, it is time to carefully and
systematically examine neural injury in humans and test the applicability of findings from animal
models. To succeed, however, we cannot view sleep apnea as an isolated process. Rather, injury
in sleep apnea is more likely the consequence of overlapping injuries from comorbid conditions.
The progress in elucidating mechanisms of neural injury is palpable, and it now seems we indeed
are closer to developing therapies to prevent and treat neural injury in obstructive sleep apnea.
PMID: 20425226 [PubMed - indexed for MEDLINE]
=====================================================================
================Cell Mol Neurobiol. 2010 Aug;30(6):929-38. Epub 2010 Apr 20.
OKEY
Relation among neuronal death, cell
proliferation and neuronal differentiation in
the gerbil main olfactory bulb after transient
cerebral ischemia.
Choi JH, Yoo KY, Park OK, Lee CH, Kim SK, Hwang IK, Lee YL, Shin HC, Won MH.
Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and
Neuroregeneration, College of Medicine, Hallym University, Chuncheon, 200-702, South Korea.
Abstract
Neurogenesis occurs during the embryonic stage and throughout life. Brain injuries such as
ischemic insults enhance cell proliferation in some areas of the brain. We examined proliferation
of newly generated cells in each layer of the gerbil main olfactory bulb (MOB) after 5 min of
transient cerebral ischemia using bromodeoxyuridine (BrdU) immunohistochemistry. Ischemiarelated neuronal death in the MOB was not detected using Fluoro-Jade B histofluorescence and
TUNEL staining. Many BrdU-positive ((+)) cells were found in the rostral migratory stream in
control and ischemic MOBs. Significant increase of BrdU(+) cells was observed in the granule
cell layer (GCL) and glomerular layer (GL) from 15 days post-ischemia, and BrdU(+) cells were
very much higher than those of the control group 30 days post-ischemia. At this time point after
ischemia/reperfusion, a few BrdU(+) cells in the GL and GCL were co-localized with
calretinin(+) cells, and many BrdU(+) cells expressed doublecortin, a marker of immature
neurons. These results indicate that cell proliferation is increased in the GCL and GL without
apparent neuronal loss from 15 days after transient cerebral ischemia in gerbils.
PMID: 20405201 [PubMed - in process]
=====================================================================================
Neurochem Int. 2010 Aug;57(1):8-15. Epub 2010 Apr 24.
OKEY
AMN082 promotes the proliferation and
differentiation of neural progenitor cells with
influence on phosphorylation of MAPK
signaling pathways.
Tian Y, Liu Y, Chen X, Kang Q, Zhang J, Shi Q, Zhang H.
Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of
Education Ministry, The State Key Subject for Physiology, Xi'an Jiaotong University College of
Medicine, China.
Abstract
Metabotropic glutamate receptors (mGluRs) are expressed in neural progenitor cells (NPCs) and
may play important roles in the neurogenesis during embryonic development and adult brain
repair following injuries. In the present study, we investigated the expression of metabotropic
glutamate receptor 7 (mGluR7) and the possible roles of this receptor in the proliferation and
differentiation of NPCs isolated from embryonic Sprague-Dawley (SD) rats. The results showed
that under the normal culture and the hypoxic condition, both mRNA and protein of mGluR 7 are
expressed in NPCs. Administration of AMN082, a selective agonist ofmGluR7, promoted the
proliferation and differentiation of NPCs. We also demonstrated that activation of JNK and ERK
signaling pathways are involved in the differentiation of NPCs into neurons following AMN082
treatment. AMN082 stimulated p-ERK and p-JNK2 expression in both normal and hypoxic
conditions at different time points. But p-p38 decreased in normoxia and increased in hypoxia
condition at 6h following treated with AMN082 activation. In conclusion, mGluR7 possesses the
potential in promoting rat NPCs proliferation and differentiation in vitro with changes in
phosphorylation of mitogen-activated protein kinases (MAPK) signaling pathways, suggesting
that mGluR7 may exert an important role in brain development and repair of the central nervous
system after injury.
PMID: 20399820 [PubMed - in process]
=====================================================================================
PLoS One. 2010 Apr 9;5(4):e10131.
OKEY
Chemical blocking of zinc ions in CNS
increases neuronal damage following
traumatic brain injury (TBI) in mice.
Doering P, Stoltenberg M, Penkowa M, Rungby J, Larsen A, Danscher G.
Institute of Anatomy, Neurobiology, University of Aarhus, Aarhus, Denmark. [email protected]
Abstract
BACKGROUND: Traumatic brain injury (TBI) is one of the leading causes of disability and
death among young people. Although much is already known about secondary brain damage the
full range of brain tissue responses to TBI remains to be elucidated. A population of neurons
located in cerebral areas associated with higher cognitive functions harbours a vesicular zinc
pool co-localized with glutamate. This zinc enriched pool of synaptic vesicles has been
hypothesized to take part in the injurious signalling cascade that follows pathological conditions
such as seizures, ischemia and traumatic brain injury. Pathological release of excess zinc ions
from pre-synaptic vesicles has been suggested to mediate cell damage/death to postsynaptic
neurons.
METHODOLOGY/PRINCIPAL FINDINGS: In order to substantiate the influence of vesicular
zinc ions on TBI, we designed a study in which damage and zinc movements were analysed in
several different ways. Twenty-four hours after TBI ZnT3-KO mice (mice without vesicular
zinc) were compared to littermate Wild Type (WT) mice (mice with vesicular zinc) with regard
to histopathology. Furthermore, in order to evaluate a possible neuro-protective dimension of
chemical blocking of vesicular zinc, we treated lesioned mice with either DEDTC or selenite.
Our study revealed that chemical blocking of vesicular zinc ions, either by chelation with
DEDTC or accumulation in zinc-selenium nanocrystals, worsened the effects on the aftermath of
TBI in the WT mice by increasing the number of necrotic and apoptotic cells within the first 24
hours after TBI, when compared to those of chemically untreated WT mice.
CONCLUSION/SIGNIFICANCE: ZnT3-KO mice revealed more damage after TBI compared to
WT controls. Following treatment with DEDTC or selenium an increase in the number of both
dead and apoptotic cells were seen in the controls within the first 24 hours after TBI while the
degree of damage in the ZnT3-KO mice remained largely unchanged. Further analyses revealed
that the damage development in the two mouse strains was almost identical after either zinc
chelation or zinc complexion therapy.
PMID: 20396380 [PubMed - in process]PMCID: PMC2852423Free PMC Article
=====================================================================================
Acta Pharmacol Sin. 2010 May;31(5):531-9. Epub 2010 Apr 12.
OKEY
Expression of a dominant-negative Rhokinase promotes neurite outgrowth in a
microenvironment mimicking injured central
nervous system.
Yang P, Wen HZ, Zhang JH.
Department of Neurobiology, Third Military Medical University, Chongqing 400038, China.
[email protected]
Abstract
AIM: To investigate whether lentiviral vector (LV)-mediated expression of a dominant negative
mutant Rho-kinase (DNROCK) could inhibit activation of the Rho/ROCK signaling pathway
and promote neurite outgrowth in a hostile microenvironment mimicking the injured central
nervous system (CNS) in vitro.
METHODS: Lentiviral stock was produced using the three-plasmid system by transfecting
HEK293 cells. Myelin prepared from rat brain was purified by two rounds of discontinuous
density gradient centrifugation and osmotic disintegration. Differentiated PC12 cells and
dissociated adult rat dorsal root ganglion (DRG) neurons were transduced with either
LV/DNROCK or LV/green fluorescent protein (GFP) and seeded on solubilized myelin proteins.
The effect of DNROCK on growth cone morphology was tested by rhodamine-conjugated
phalloidin staining. Expression of DNROCK was determined by immunoblotting. The length of
the longest neurite, the percentage of neurite-bearing neurons, or the total process outgrowth for
all transduced neurons were measured by using the Scion image analysis program.
RESULTS: Transduction of DNROCK inhibited serum-induced stress fiber formation in NIH
3T3 cells and induced enlargement of cell bodies and decreased the phosphorylation levels of
MYPT1 in HeLa cells. LV/DNROCK blocked myelin-induced increase in ROCK translocation
from cytosol to membrane in LV/GFP-treated PC12 cells. DNROCK promotes neurite outgrowth
of differentiated PC12 cells and DRG neurons on myelin protein. LV/DNROCK-transduced
PC12 cells had longer neurites than LV/GFP-transduced cells (39.18+/-2.19 microm vs 29.32+/1.7 microm, P<0.01) on myelin-coated coverslips. Furthermore, a significantly higher percentage
of LV/DNROCK-transduced cells had extended neurites than LV/GFP-transduced cells
(63.75%+/-8.03% vs 16.3%+/-3.70%, P<0.01). LV/DNROCK-transduced DRG neurons had
longer neurite length (325.22+/-10.8 microm vs 202.47+/-9.3 microm, P<0.01) and more primary
neurites per cell than those in LV/GFP-transduced cells plated on myelin and laminin (7.8+/-1.25
vs 4.84+/-1.45, P<0.01) or on laminin alone (5.2+/-1.88). LV/DNROCK-transduced cells had
significantly larger growth cones (33.12+/-1.06 microm(2)) than LV/GFP-pretreated cells
(23.72+/-1.22 microm(2)).
CONCLUSION: These results indicate that blocking the RhoA/ROCK signaling pathway by
expression of DNROCK is effective in facilitating neurite outgrowth in a microenvironment
mimicking injury of central nervous system.
PMID: 20383168 [PubMed - indexed for MEDLINE]
=====================================================================================
Brain. 2010 Apr;133(Pt 4):1013-25.
Spinal cord injury causes a wide-spread,
persistent loss of Kir4.1 and glutamate
transporter 1: benefit of 17 beta-oestradiol
treatment.
Olsen ML, Campbell SC, McFerrin MB, Floyd CL, Sontheimer H.
Department of Neurobiology, Centre for Glial Biology in Medicine, University of Alabama at
Birmingham, 1719 6th Ave. S., CIRC 425, Birmingham, AL 35294, USA.
Abstract
During neuronal activity astrocytes function to remove extracellular increases in potassium,
which are largely mediated by the inwardly-rectifying potassium channel Kir4.1, and to take up
excess glutamate via glutamate transporter 1, a glial-specific glutamate transporter. Here we
demonstrate that expression of both of these proteins is reduced by nearly 80% following a crush
spinal cord injury in adult male rats, 7 days post-injury. This loss extended to spinal segments
several millimetres rostral and caudal to the lesion epicentre, and persisted at 4 weeks postinjury. Importantly, we demonstrate that loss of these two proteins is not a direct result of
astrocyte loss, as immunohistochemistry at 7 days and western blots at 4 weeks demonstrate a
marked up-regulation in glial fibrillary acidic protein expression. Kir4.1 and glutamate
transporter 1 expression were partially rescued by post-spinal cord injury administration of
physiological levels of 17beta-oestradiol (0.08 mg/kg/day) in vivo. Utilizing an in vitro culture
system we demonstrate that 17beta-oestradiol treatment (50 nM) is sufficient to increase
glutamate transporter 1 protein expression in spinal cord astrocytes. This increase in glutamate
transporter 1 protein expression was reversed and Kir4.1 expression reduced in the presence of
an oestrogen receptor antagonist, Fulvestrant 182,780 suggesting a direct translational regulation
of Kir4.1 and glutamate transporter 1 via genomic oestrogen receptors. Using whole-cell patchclamp recordings in cultured spinal cord astrocytes, we show that changes in protein expression
following oestrogen application led to functional changes in Kir4.1 mediated currents. These
findings suggest that the neuroprotective benefits previously seen with 17beta-oestradiol after
spinal cord injury may be in part due to increased Kir4.1 and glutamate transporter 1 expression
in astrocytes leading to improved potassium and glutamate homeostasis.
PMID: 20375134 [PubMed - indexed for MEDLINE]PMCID: PMC2850584 [Available on
2011/4/1]
=====================================================================
================Int J Neurosci. 2010 Mar;120(3):192-200.
Proliferation, migration, and neuronal
differentiation of the endogenous neural
progenitors in hippocampus after fimbria
fornix transection.
Zou L, Jin G, Zhang X, Qin J, Zhu H, Tian M, Tan X.
Department of Anatomy and Neurobiology, Jiangsu Key Laboratory of Neuroregeneration,
Nantong University, Nantong, China.
Abstract
Neurogenesis in the hippocampus continues throughout adult life and can be regulated by the
local microenvironment. To determine whether denervation stimulates neurogenesis in
hippocampus, proliferation, migration, and differentiation of local neural stem cells (NSCs) in
dentate gyrus was investigated after fimbria fornix transection. In the denervated hippocampus,
NSCs proliferated markedly and migrated along the subgranular layer, and more newborn cells
differentiated into neurons or astrocytes. After denervation, more newborn cells in the
deafferented hippocampus expressed Brn-4 and differentiated into beta-Tubulin III positive
neurons. It is concluded that the local NSCs in hippocampus may proliferate and migrate into
granule cell layer, in which changes in the deafferented hippocampus provided a suitable
microenvironment for hippocampal neurogenesis and the increased Brn-4 in denervated
hippocampus may be involved in this process.
PMID: 20374086 [PubMed - indexed for MEDLINE]
=====================================================================
================Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7586-91. Epub 2010 Apr
5.
Dock3 induces axonal outgrowth by
stimulating membrane recruitment of the
WAVE complex.
Namekata K, Harada C, Taya C, Guo X, Kimura H, Parada LF, Harada T.
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu,
Tokyo 183-8526, Japan.
Abstract
Atypical Rho-guanine nucleotide exchange factors (Rho-GEFs) that contain Dock homology
regions (DHR-1 and DHR-2) are expressed in a variety of tissues; however, their functions and
mechanisms of action remain unclear. We identify key conserved amino acids in the DHR-2
domain that are critical for the catalytic activity of Dock-GEFs (Dock1-4). We further
demonstrate that Dock-GEFs directly associate with WASP family verprolin-homologous
(WAVE) proteins through the DHR-1 domain. Brain-derived neurotrophic factor (BDNF)-TrkB
signaling recruits the Dock3/WAVE1 complex to the plasma membrane, whereupon Dock3
activates Rac and dissociates from the WAVE complex in a phosphorylation-dependent manner.
BDNF induces axonal sprouting through Dock-dependent Rac activation, and adult transgenic
mice overexpressing Dock3 exhibit enhanced optic nerve regeneration after injury without
affecting WAVE expression levels. Our results highlight a unique mechanism through which
Dock-GEFs achieve spatial and temporal restriction of WAVE signaling, and identify Dock-GEF
activity as a potential therapeutic target for axonal regeneration.
PMID: 20368433 [PubMed - indexed for MEDLINE]PMCID: PMC2867726Free PMC Article
=====================================================================
================Exp Neurol. 2010 Jul;224(1):241-51. Epub 2010 Apr 1.
The effects of cyclosporin-A on axonal
conduction deficits following traumatic brain
injury in adult rats.
Colley BS, Phillips LL, Reeves TM.
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth
University Medical Center, Richmond, VA 23298, USA.
Abstract
Immunophilin ligands, including cyclosporin-A (CsA), have been shown to be neuroprotective in
experimental models of traumatic brain injury (TBI) and to attenuate the severity of traumatic
axonal injury. Prior studies have documented CsA treatment to reduce essential components of
posttraumatic axonal pathology, including impaired axoplasmic transport, spectrin proteolysis,
and axonal swelling. However, the effects of CsA administration on axonal function, following
TBI, have not been evaluated. The present study assessed the effects of CsA treatment on
compound action potentials (CAPs) evoked in corpus callosum of adult rats following midline
fluid percussion injury. Rats received a 20 mg/kg bolus of CsA, or cremaphor vehicle, at either
15 min or 1 h postinjury, and at 24 h postinjury CAP recording was conducted in coronal brain
slices. To elucidate how injury and CsA treatments affect specific populations of axons, CAP
waveforms generated largely by myelinated axons (N1) were analyzed separately from the CAP
signal, which predominantly reflects activity in unmyelinated axons (N2). CsA administration at
15 min postinjury resulted in significant protection of CAP area, and this effect was more
pronounced in N1, than in the N2, CAP component. This treatment also significantly protected
against TBI-induced reductions in high-frequency responding of the N1 CAP signal. In contrast,
CsA treatment at 1 h did not significantly protect CAPs but was associated with atypical
waveforms in N1 CAPs, including decreased CAP duration and reduced refractoriness. The
present findings also support growing evidence that myelinated and unmyelinated axons respond
differentially to injury and neuroprotective compounds.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20362574 [PubMed - indexed for MEDLINE]PMCID: PMC2885519 [Available on
2011/7/1]
=====================================================================================
Stroke. 2010 May;41(5):898-904. Epub 2010 Apr 1.
OKEY
Key role of CD36 in Toll-like receptor 2
signaling in cerebral ischemia.
Abe T, Shimamura M, Jackman K, Kurinami H, Anrather J, Zhou P, Iadecola C.
Division of Neurobiology, Weill Cornell Medical College, 407 E 61st St, Room RR303, New
York, NY 10065, USA.
Abstract
BACKGROUND AND PURPOSE: Toll-like receptors (TLRs) and the scavenger receptor CD36
are key molecular sensors for the innate immune response to invading pathogens. However,
these receptors may also recognize endogenous "danger signals" generated during brain injury,
such as cerebral ischemia, and trigger a maladaptive inflammatory reaction. Indeed, CD36 and
TLR2 and 4 are involved in the inflammation and related tissue damage caused by brain
ischemia. Because CD36 may act as a coreceptor for TLR2 heterodimers (TLR2/1 or TLR2/6),
we tested whether such interaction plays a role in ischemic brain injury.
METHODS: The TLR activators FSL-1 (TLR2/6), Pam3 (TLR2/1), or lipopolysaccharide
(TLR4) were injected intracerebroventricularly into wild-type or CD36-null mice, and
inflammatory gene expression was assessed in the brain. The effect of TLR activators on the
infarct produced by transient middle cerebral artery occlusion was also studied.
RESULTS: The inflammatory response induced by TLR2/1 activation, but not TLR2/6 or TLR4
activation, was suppressed in CD36-null mice. Similarly, TLR2/1 activation failed to increase
infarct volume in CD36-null mice, whereas TLR2/6 or TLR4 activation exacerbated
postischemic inflammation and increased infarct volume. In contrast, the systemic inflammatory
response evoked by TLR2/6 activation, but not by TLR2/1 activation, was suppressed in CD36null mice.
CONCLUSIONS: In the brain, TLR2/1 signaling requires CD36. The cooperative signaling of
TLR2/1 and CD36 is a critical factor in the inflammatory response and tissue damage evoked by
cerebral ischemia. Thus, suppression of CD36-TLR2/1 signaling could be a valuable approach to
minimize postischemic inflammation and the attendant brain injury.
PMID: 20360550 [PubMed - indexed for MEDLINE]PMCID: PMC2950279Free PMC Article
=====================================================================================
Stroke. 2010 May;41(5):1018-26. Epub 2010 Apr 1.
OKEY
Preservation of GABAA receptor function by
PTEN inhibition protects against neuronal
death in ischemic stroke.
Liu B, Li L, Zhang Q, Chang N, Wang D, Shan Y, Li L, Wang H, Feng H, Zhang L, Brann DW,
Wan Q.
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health
Network, Toronto, Canada.
Abstract
BACKGROUND AND PURPOSE: Downregulation of the tumor suppressor, phosphatase and
tensin homolog deleted on chromosome 10 (PTEN), is thought to be a novel neuroprotective
strategy in ischemic stroke, but the underlying mechanisms remain unclear. In this study, we
aimed to validate the use of PTEN regulation of gamma-aminobutyric acid subtype A receptors
(GABA(A)Rs) as a molecular target for the treatment of ischemic stroke. Because suppression of
GABA(A)Rs contributes to ischemic neuron death, describing the intracellular signaling that
interacts with GABA(A)Rs in ischemic neurons would provide a molecular basis for novel
stroke therapies.
METHODS: We measured surface GABA(A)R expression by immunocytochemical labeling and
surface protein biotinylation assay. Knockdown and overexpression approaches were used to test
the effects of PTEN on the expression and function of GABA(A)Rs. Neuronal death was
detected in both in vitro and in vivo stroke models.
RESULTS: The knockdown and overexpression approaches provided the first evidence that
PTEN negatively regulated membrane expression and function of GABA(A)Rs in rat
hippocampal neurons. Importantly, we demonstrated that a PTEN inhibitor prevented the
reduction of surface GABA(A)Rs in injured hippocampal neurons subjected to oxygen-glucose
deprivation, an in vitro insult that mimics ischemic injury, whereas a GABA(A)R antagonist
significantly reduced this PTEN inhibitor-induced neuroprotection in both the in vitro and in
vivo ischemic stroke models.
CONCLUSIONS: Our study provides direct evidence that downregulation of PTEN protects
against ischemic neuron death by preserving GABA(A)R function. Targeting this pathway may
be an effective strategy for development of selective, potent stroke treatments.
PMID: 20360540 [PubMed - indexed for MEDLINE]
=====================================================================================
Exp Neurol. 2010 Jul;224(1):207-18. Epub 2010 Mar 29.
OKEY
Neuroprotection by glutamate receptor
antagonists against seizure-induced
excitotoxic cell death in the aging brain.
Schauwecker PE.
Department of Cell and Neurobiology, USC Keck School of Medicine, 1333 San Pablo Street,
BMT 403, Los Angeles, CA 90089-9112, USA. [email protected]
Abstract
We previously have identified phenotypic differences in susceptibility to hippocampal seizureinduced cell death among two inbred strains of mice. We have also reported that the age-related
increased susceptibility to the neurotoxic effects of seizure-induced injury is regulated in a
strain-dependent manner. In the present study, we wanted to begin to determine the
pharmacological mechanism that contributes to variability in the response to the neurotoxic
effects of kainate. Thus, we compared the effects of the NMDA receptor antagonist, MK-801
and of the AMPA receptor antagonist NBQX on hippocampal damage in the kainate model of
seizure-induced excitotoxic cell death in young, middle-aged, and aged C57BL/6 and FVB/N
mice, when given 90 min following kainate-induced status epilepticus. Following kainate
injections, mice were scored for seizure activity and brains from mice in each age and antagonist
group were processed for light microscopic histopathologic evaluation 7 days following kainate
administration to evaluate the severity of seizure-induced injury. Administration of MK-801
significantly reduced the extent of hippocampal damage in young, mature and aged FVB/N mice,
while application of NBQX was only effective at attenuating cell death in young and aged mice
throughout all hippocampal subfields. Our results suggest that both NMDA and non-NMDA
receptors are involved in kainate-induced cell death in the mouse and suggest that aging may
differentially affect the ability of neuroprotectants to protect against hippocampal damage.
Differences in the effectiveness of these two antagonists could result from differential regulation
of glutamatergic neurotransmitter systems or ion channel specificity.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20353782 [PubMed - indexed for MEDLINE]PMCID: PMC2885455 [Available on
2011/7/1]
=====================================================================================
Neurobiol Dis. 2010 Aug;39(2):127-37. Epub 2010 Mar 27.
OKEY
17beta-estradiol protects male mice from
cuprizone-induced demyelination and
oligodendrocyte loss.
Taylor LC, Puranam K, Gilmore W, Ting JP, Matsushima GK.
Curriculum in Neurobiology, University of North Carolina-CH, Chapel Hill, NC 27599, USA.
Abstract
In addition to regulating reproductive functions in the brain and periphery, estrogen has tropic
and neuroprotective functions in the central nervous system (CNS). Estrogen administration has
been demonstrated to provide protection in several animal models of CNS disorders, including
stroke, brain injury, epilepsy, Parkinson's disease, Alzheimer's disease, age-related cognitive
decline and multiple sclerosis. Here, we use a model of toxin-induced oligodendrocyte death
which results in demyelination, reactive gliosis, recruitment of oligodendrocyte precursor cells
and subsequent remyelination to study the potential benefit of 17beta-estradiol (E2)
administration in male mice. The results indicate that E2 partially ameliorates loss of
oligodendrocytes and demyelination in the corpus callosum. This protection is accompanied by a
delay in microglia accumulation as well as reduced mRNA expression of the pro-inflammatory
cytokine, tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-1 (IGF-1). E2
did not significantly alter the accumulation of astrocytes or oligodendrocyte precursor cells, or
remyelination. These data obtained from a toxin-induced, T cell-independent model using male
mice provide an expanded view of the beneficial effects of estrogen on oligodendrocyte and
myelin preservation.
PMID: 20347981 [PubMed - indexed for MEDLINE]PMCID: PMC2891426 [Available on
2011/8/1]
=====================================================================================
J Neurochem. 2010 Mar 14. [Epub ahead of print]
OKEY
Anoxia leads to a rapid translocation of
human trypsinogen 4 to the plasma
membrane of cultured astrocytes.
Tárnok K, Szilágyi L, Berki T, Németh P, Gráf L, Schlett K.
Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, Hungary.
Abstract
J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06685.x Abstract Trypsinogen 4 is specifically
expressed in the human brain, mainly by astroglial cells. Although its exact role in the nervous
tissue is yet unclear, trypsin 4-mediated pathological processes were suggested in Alzheimer's
disease, multiple sclerosis and ischemic injury. In the present study, we analyzed the intracellular
distribution of fluorescently tagged human trypsinogen 4 isoforms during normal and anoxic
conditions in transfected mouse primary astrocytes. Our results show that initiation of anoxic
milieu by the combined action of KCN treatment and glucose deprivation rapidly leads to the
association of leader peptide containing trypsinogen 4 constructs to the plasma membrane. Using
rhodamine 110 bis-(CBZ-L-isoleucyl-L-prolyl-L-arginine amide), a synthetic chromogen peptide
substrate of trypsin, we show that anoxia can promote extracellular activation of trypsinogen 4
indicating that extracellular activation of human trypsinogen 4 can be an important component in
neuropathological changes of the injured human brain.
PMID: 20345763 [PubMed - as supplied by publisher]
=====================================================================================
J Neurotrauma. 2010 May;27(5):889-99.
OKEY
ICANG
Diffuse brain injury elevates tonic glutamate
levels and potassium-evoked glutamate
release in discrete brain regions at two days
post-injury: an enzyme-based microelectrode
array study.
Hinzman JM, Thomas TC, Burmeister JJ, Quintero JE, Huettl P, Pomerleau F, Gerhardt GA,
Lifshitz J.
Department of Anatomy and Neurobiology, University of Kentucky Chandler Medical Center,
Lexington, Kentucky 40536-0509, USA.
Abstract
Traumatic brain injury (TBI) survivors often suffer from a wide range of post-traumatic deficits,
including impairments in behavioral, cognitive, and motor function. Regulation of glutamate
signaling is vital for proper neuronal excitation in the central nervous system. Without proper
regulation, increases in extracellular glutamate can contribute to the pathophysiology and
neurological dysfunction seen in TBI. In the present studies, enzyme-based microelectrode
arrays (MEAs) that selectively measure extracellular glutamate at 2 Hz enabled the examination
of tonic glutamate levels and potassium chloride (KCl)-evoked glutamate release in the
prefrontal cortex, dentate gyrus, and striatum of adult male rats 2 days after mild or moderate
midline fluid percussion brain injury. Moderate brain injury significantly increased tonic
extracellular glutamate levels by 256% in the dentate gyrus and 178% in the dorsal striatum. In
the dorsal striatum, mild brain injury significantly increased tonic glutamate levels by 200%.
Tonic glutamate levels were significantly correlated with injury severity in the dentate gyrus and
striatum. The amplitudes of KCl-evoked glutamate release were increased significantly only in
the striatum after moderate injury, with a 249% increase seen in the dorsal striatum. Thus, with
the MEAs, we measured discrete regional changes in both tonic and KCl-evoked glutamate
signaling, which were dependent on injury severity. Future studies may reveal the specific
mechanisms responsible for glutamate dysregulation in the post-traumatic period, and may
provide novel therapeutic means to improve outcomes after TBI.
PMID: 20233041 [PubMed - in process]PMCID: PMC2943939 [Available on 2011/5/1]
=====================================================================================
J Neuroinflammation. 2010 Mar 11;7:19.
Serum IL-6: a candidate biomarker for
intracranial pressure elevation following
isolated traumatic brain injury.
Hergenroeder GW, Moore AN, McCoy JP Jr, Samsel L, Ward NH 3rd, Clifton GL, Dash PK.
The Department of Neurobiology and Anatomy, The University of Texas Medical School,
Houston, Texas, USA. [email protected]
Abstract
BACKGROUND: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary
event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion,
reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be
implanted to monitor ICP, there is no clinically proven method for determining a patient's risk
for developing this pathology.
METHODS: In the present study, we employed antibody array and Luminex-based screening
methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers
and in severe TBI patients (GCS<or=8) with or without incidence of elevated intracranial
pressure (ICP). De-identified samples and ELISAs were used to confirm the sensitivity and
specificity of IL-6 as a prognostic marker of elevated ICP in both isolated TBI patients, and
polytrauma patients with TBI.
RESULTS: Consistent with previous reports, we observed sustained increases in IL-6 levels in
TBI patients irrespective of their ICP status. However, the group of patients who subsequently
experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of
injury as compared to the patients whose ICP remained <or=20 mm Hg. When blinded samples
(n = 22) were assessed, a serum IL-6 cut-off of <5 pg/ml correctly identified 100% of all the
healthy volunteers, a cut-off of >128 pg/ml correctly identified 85% of isolated TBI patients who
subsequently developed elevated ICP, and values between these cut-off values correctly
identified 75% of all patients whose ICP remained <or=20 mm Hg throughout the study period.
In contrast, the marker had no prognostic value in predicting elevated ICP in polytrauma patients
with TBI. When the levels of serum IL-6 were assessed in patients with orthopedic injury (n = 7)
in the absence of TBI, a significant increase was found in these patients compared to healthy
volunteers, albeit lower than that observed in TBI patients.
CONCLUSIONS: Our results suggest that serum IL-6 can be used for the differential diagnosis
of elevated ICP in isolated TBI.
PMID: 20222971 [PubMed - indexed for MEDLINE]PMCID: PMC2853529Free PMC Article
=====================================================================================
J Cereb Blood Flow Metab. 2010 Jun;30(6):1247-60. Epub 2010 Mar 10.
Acid-sensing ion channels in acidosis-induced
injury of human brain neurons.
Li M, Inoue K, Branigan D, Kratzer E, Hansen JC, Chen JW, Simon RP, Xiong ZG.
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Abstract
Acidosis is a common feature of the human brain during ischemic stroke and is known to cause
neuronal injury. However, the mechanism underlying acidosis-mediated injury of the human
brain remains elusive. We show that a decrease in the extracellular pH evoked inward currents
characteristic of acid-sensing ion channels (ASICs) and increased intracellular Ca(2+) in cultured
human cortical neurons. Acid-sensing ion channels in human cortical neurons show
electrophysiological and pharmacological properties distinct from those in neurons of the rodent
brain. Reverse transcriptase-PCR and western blot detected a high level of the ASIC1a subunit
with little or no expression of other ASIC subunits. Treatment of human cortical neurons with
acidic solution induced substantial cell injury, which was attenuated by the ASIC1a blockade.
Thus, functional homomeric ASIC1a channels are predominantly expressed in neurons from the
human brain. Activation of these channels has an important role in acidosis-mediated injury of
human brain neurons.
PMID: 20216553 [PubMed - indexed for MEDLINE]PMCID: PMC2916164 [Available on
2011/6/1]
=====================================================================================
Neuroimage. 2010 Jun;51(2):521-30. Epub 2010 Mar 6.
Diffusion tensor MRI of axonal plasticity in
the rat hippocampus.
Laitinen T, Sierra A, Pitkänen A, Gröhn O.
Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of
Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
Abstract
The aim of this study was to explore non-invasive imaging methods to detect post-injury
structural axonal plasticity. Brain injury was launched by status epilepticus induced by
intraperitoneal injection of either kainic acid or pilocarpine. Several months later, ex vivo
diffusion tensor magnetic resonance imaging (DTI) showed increased FA in the dentate gyrus of
both kainic acid (p<0.01) and pilocarpine animals (p<0.01). Importantly, FA changes correlated
(p<0.01) with histologically verified axonal plasticity of myelinated and non-myelinated
neuronal fibers. The changes observed in DTI parameters ex vivo in the septal dentate gyrus
were also seen by in vivo DTI. As DTI is completely a non-invasive imaging method, these
results may pave the way for non-invasive in vivo imaging of axonal plasticity after brain insults.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20211740 [PubMed - indexed for MEDLINE]
=====================================================================================
Curr Neuropharmacol. 2009 Sep;7(3):228-37.
Adenosine neuromodulation and traumatic
brain injury.
Lusardi TA.
R. S. Dow Neurobiology Laboratory, Portland OR, USA. [email protected]
Abstract
Adenosine is a ubiquitous signaling molecule, with widespread activity across all organ systems.
There is evidence that adenosine regulation is a significant factor in traumatic brain injury (TBI)
onset, recovery, and outcome, and a growing body of experimental work examining the
therapeutic potential of adenosine neuromodulation in the treatment of TBI. In the central
nervous system (CNS), adenosine (dys)regulation has been demonstrated following TBI, and
correlated to several TBI pathologies, including impaired cerebral hemodynamics, anaerobic
metabolism, and inflammation. In addition to acute pathologies, adenosine function has been
implicated in TBI comorbidities, such as cognitive deficits, psychiatric function, and posttraumatic epilepsy. This review presents studies in TBI as well as adenosine-related mechanisms
in co-morbidities of and unfavorable outcomes resulting from TBI. While the exact role of the
adenosine system following TBI remains unclear, there is increasing evidence that a thorough
understanding of adenosine signaling will be critical to the development of diagnostic and
therapeutic tools for the treatment of TBI.
PMID: 20190964 [PubMed]PMCID: PMC2769006Free PMC Article
=====================================================================================
J Biol Chem. 2010 Apr 23;285(17):13002-11. Epub 2010 Feb 25.
Activation of acid-sensing ion channel 1a
(ASIC1a) by surface trafficking.
Chai S, Li M, Branigan D, Xiong ZG, Simon RP.
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
[email protected]
Abstract
Acid-sensing ion channels (ASICs) are voltage-independent Na(+) channels activated by
extracellular protons. ASIC1a is expressed in neurons in mammalian brain and is implicated in
long term potentiation of synaptic transmission that contributes to learning and memory. In
ischemic brain injury, however, activation of this Ca(2+)-permeable channel plays a critical role
in acidosis-mediated, glutamate-independent, Ca(2+) toxicity. We report here the identification
of insulin as a regulator of ASIC1a surface expression. In modeled ischemia using Chinese
hamster ovary cells, serum depletion caused a significant increase in ASIC1a surface expression
that resulted in the potentiation of ASIC1a activity. Among the components of serum, insulin
was identified as the key factor that maintains a low level of ASIC1a on the plasma membrane.
Neurons subjected to insulin depletion increased surface expression of ASIC1a with resultant
potentiation of ASIC1a currents. Intracellularly, ASIC1a is predominantly localized to the
endoplasmic reticulum in Chinese hamster ovary cells, and this intracellular localization is also
observed in neurons. Under conditions of serum or insulin depletion, the intracellular ASIC1a is
translocated to the cell surface, increasing the surface expression level. These results reveal an
important trafficking mechanism of ASIC1a that is relevant to both the normal physiology and
the pathological activity of this channel.
PMID: 20185828 [PubMed - indexed for MEDLINE]PMCID: PMC2857104 [Available on
2011/4/23]
=====================================================================================
Front Neuroengineering. 2010 Feb 8;2:18.
Bridging the Divide between Neuroprosthetic
Design, Tissue Engineering and
Neurobiology.
Leach JB, Achyuta AK, Murthy SK.
Department of Chemical and Biochemical Engineering, University of Maryland Baltimore, MD,
USA.
Abstract
Neuroprosthetic devices have made a major impact in the treatment of a variety of disorders such
as paralysis and stroke. However, a major impediment in the advancement of this technology is
the challenge of maintaining device performance during chronic implantation (months to years)
due to complex intrinsic host responses such as gliosis or glial scarring. The objective of this
review is to bring together research communities in neurobiology, tissue engineering, and
neuroprosthetics to address the major obstacles encountered in the translation of neuroprosthetics
technology into long-term clinical use. This article draws connections between specific
challenges faced by current neuroprosthetics technology and recent advances in the areas of
nerve tissue engineering and neurobiology. Within the context of the device-nervous system
interface and central nervous system implants, areas of synergistic opportunity are discussed,
including platforms to present cells with multiple cues, controlled delivery of bioactive factors,
three-dimensional constructs and in vitro models of gliosis and brain injury, nerve regeneration
strategies, and neural stem/progenitor cell biology. Finally, recent insights gained from the fields
of developmental neurobiology and cancer biology are discussed as examples of exciting new
biological knowledge that may provide fresh inspiration toward novel technologies to address the
complexities associated with long-term neuroprosthetic device performance.
PMID: 20161810 [PubMed - in process]PMCID: PMC2821180Free PMC Article
=====================================================================================
Curr Opin Crit Care. 2010 Feb 12. [Epub ahead of print]
Imaging brain trauma.
Duckworth JL, Stevens RD.
aDepartment of Anesthesiology Critical Care Medicine, USA bDepartment of Neurology, USA
cDepartment of Neurosurgery, USA dDepartment of Radiology, Johns Hopkins University
School of Medicine, USA eF. M. Kirby Research Center for Functional Brain Imaging, Kennedy
Krieger Institute, Baltimore, Maryland, USA.
Abstract
PURPOSE OF REVIEW: Traumatic brain injury (TBI) is a leading cause of death and long-term
cognitive and behavioral dysfunction in children and young adults, yet effective treatments are
lacking, in part because critical aspects of TBI neurobiology and natural history are not
understood. We review recent advances in neuroimaging and discuss how they are helping to
address these fundamental gaps.
RECENT FINDINGS: Novel imaging methods provide detailed information on how TBI affects
anatomical integrity (diffusion tensor imaging; voxel-based morphometry; susceptibilityweighted imaging, magnetization transfer imaging), metabolic activity (magnetic resonance
spectroscopy), perfusion (positron emission tomography, perfusion computed tomography,
perfusion magnetic resonance), and patterns of functional activation (functional magnetic
resonance imaging). Individually and collectively, these methods can significantly enhance TBI
diagnosis and outcome prediction.
SUMMARY: Refinements in neuroimaging offer a window into the complex neuroanatomical
and neurophysiological disturbances induced by TBI. Research is needed to understand how
these alterations evolve with time and in response to therapeutic interventions.
PMID: 20160645 [PubMed - as supplied by publisher]
=====================================================================================
J Cereb Blood Flow Metab. 2010 Jul;30(7):1318-28. Epub 2010 Feb 10.
Cerebral blood volume alterations in the
perilesional areas in the rat brain after
traumatic brain injury--comparison with
behavioral outcome.
Immonen R, Heikkinen T, Tähtivaara L, Nurmi A, Stenius TK, Puoliväli J, Tuinstra T, Phinney
AL, Van Vliet B, Yrjänheikki J, Gröhn O.
Biomedical NMR Group, Department of Neurobiology, A.I. Virtanen Institute for Molecular
Sciences, University of Eastern Finland, Kuopio, Finland. [email protected]
Abstract
In the traumatic brain injury (TBI) the initial impact causes both primary injury, and launches
secondary injury cascades. One consequence, and a factor that may contribute to these secondary
changes and functional outcome, is altered hemodynamics. The relative cerebral blood volume
(CBV) changes in rat brain after severe controlled cortical impact injury were characterized to
assess their interrelations with motor function impairment. Magnetic resonance imaging (MRI)
was performed 1, 2, 4 h, and 1, 2, 3, 4, 7, and 14 days after TBI to quantify CBV and water
diffusion. Neuroscore test was conducted before, and 2, 7, and 14 days after the TBI. We found
distinct temporal profile of CBV in the perilesional area, hippocampus, and in the primary lesion.
In all regions, the first response was drop of CBV. Perifocal CBV was reduced for over 4 days
thereafter gradually recovering. After the initial drop, the hippocampal CBV was increased for 2
weeks. Neuroscore demonstrated severely impaired motor functions 2 days after injury (33%
decrease), which then slowly recovered in 2 weeks. This recovery parallelled the recovery of
perifocal CBV. CBV MRI can detect cerebrovascular pathophysiology after TBI in the
vulnerable perilesional area, which seems to potentially associate with time course of sensorymotor deficit.
PMID: 20145657 [PubMed - indexed for MEDLINE]
=====================================================================================
Neurotherapeutics. 2010 Jan;7(1):100-14.
Biomarkers for the diagnosis, prognosis, and
evaluation of treatment efficacy for traumatic
brain injury.
Dash PK, Zhao J, Hergenroeder G, Moore AN.
Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston,
Texas 77225, USA. [email protected]
Abstract
Traumatic brain injury (TBI) remains a serious health concern, and TBI is one of the leading
causes of death and disability, especially among young adults. Although preventive education,
increased usage of safety devices, and TBI management have dramatically increased the
potential for surviving a brain injury, there is still a need to develop reliable methods to diagnose
TBI, the secondary pathologies associated with TBI, and predicting the outcomes of TBI.
Biomarkers (changes of amount or activity in a biomolecule that reflect injury or disease) have
shown promise in the diagnosis of several conditions, including cancer, heart failure, infection,
and genetic disorders. A variety of proteins, small molecules, and lipid products have been
proposed as potential biomarkers of brain damage from TBI. Although some of these changes
have been reported to correlate with mortality and outcome, further research is required to
identify prognostic biomarkers. This need is punctuated in mild injuries that cannot be readily
detected using current techniques, as well as in defining patient risk for developing TBIassociated secondary injuries.
Copyright 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by
Elsevier Inc. All rights reserved.
PMID: 20129502 [PubMed - indexed for MEDLINE]
=====================================================================================
Brain. 2010 Mar;133(Pt 3):808-21. Epub 2010 Jan 31.
Reactive microgliosis: extracellular microcalpain and microglia-mediated
dopaminergic neurotoxicity.
Levesque S, Wilson B, Gregoria V, Thorpe LB, Dallas S, Polikov VS, Hong JS, Block ML.
Department of Anatomy & Neurobiology, Sanger Hall, Room 9-048, 1101 E. Marshall Street,
Virginia Commonwealth University Medical Campus, Box 980709, Richmond, VA 23298-0709,
USA.
Abstract
Microglia, the innate immune cells in the brain, can become chronically activated in response to
dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by
further neuron damage (reactive microgliosis), which is implicated in the progressive nature of
Parkinson's disease. Here, we use an in vitro approach to separate neuron injury factors from the
cellular actors of reactive microgliosis and discover molecular signals responsible for chronic
and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-
phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury
factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed
mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate
oxidase. mu-Calpain was identified as a key signal released from damaged neurons, causing
selective dopaminergic neuron death through activation of microglial nicotinamide adenine
dinucleotide phosphate oxidase and superoxide production. These findings suggest that
dopaminergic neurons may be inherently susceptible to the pro-inflammatory effects of neuron
damage, i.e. reactive microgliosis, providing much needed insight into the chronic nature of
Parkinson's disease.
PMID: 20123724 [PubMed - indexed for MEDLINE]PMCID: PMC2860703 [Available on
2011/3/1]
=====================================================================================
Brain Res Rev. 2010 May;63(1-2):47-59. Epub 2010 Jan 21.
What determines neurogenic competence in
glia?
Costa MR, Götz M, Berninger B.
Edmond and Lily Safra International Institute of Neuroscience of Natal, 59066-060 Natal, Brazil.
Abstract
One of the most intriguing discoveries during the last decade of developmental neurobiology is
the fact that both in the developing and adult nervous system neural stem cells often turn out to
have a glial identity: Radial glia generates neurons in the developing telencephalon of fish, birds
and mammals and astro/radial glial stem cells in specialized neurogenic zones give rise to new
neurons throughout life. What are the extrinsic signals acting on and the intrinsic signals acting
within these glial populations endowing these with a neurogenic potential, whilst most other glia
seemingly lack it? Studies on postnatal astroglia shed interesting light on this question as they
are the intermediate between neurogenic radial glia and mature parenchymal astrocytes. At least
in vitro their decision to acquire a glial fate is not yet irrevocable as forced expression of a single
neurogenic transcription factor enables them to transgress their lineage and to give rise to fully
functional neurons acquiring specific subtype characteristics. But even bona fide non-neurogenic
glia in the adult nervous system can regain some of their radial glial heritage following injury as
exemplified by reactive astroglia in the cerebral cortex and Müller glia in the retina. In this
review first we will follow the direction of the physiological times' arrow, along which radial
glia become transformed on one side into mature astrocytes gradually losing their neurogenic
potential, while some of them seem to escape this dire destiny to settle in the few neurogenic
oases of the adult brain where they generate neurons and glia throughout life. But we will also
see how pathophysiological conditions partially can reverse the arrow of time reactivating the
parenchymal astroglia to re-acquire some of the hallmarks of neural stem cells or progenitors.
We will close this review with some thoughts on the surprising compatibility of the co-existence
of a neural stem cell and glial identity within the very same cell from the perspective of the
concept of transcriptional core networks.
Copyright 2010 Elsevier B.V. All rights reserved.
PMID: 20096728 [PubMed - indexed for MEDLINE]
=====================================================================================
J Neurosci Res. 2010 Jun;88(8):1719-26.
Serum ceruloplasmin and copper are early
biomarkers for traumatic brain injuryassociated elevated intracranial pressure.
Dash PK, Redell JB, Hergenroeder G, Zhao J, Clifton GL, Moore A.
Department of Neurobiology and Anatomy, The University of Texas Medical School, Houston,
TX 77225, USA. [email protected]
Abstract
High intracranial pressure (ICP) is a prominent secondary pathology after traumatic brain injury
(TBI) and is a major contributor to morbidity and mortality. Currently, there are no clinically
proven methods for predicting which TBI patients will develop high ICP. In the present study,
we examined whether the serum levels of the copper-binding protein ceruloplasmin are
differentially altered in patients with elevated ICP (> or =25 mmHg) vs. those whose ICP
remained below 20 mmHg throughout the study period. Consistent with its role as an acutephase reactant, we found that ceruloplasmin levels were significantly increased by 3 days postTBI compared with healthy volunteers. However, prior to this delayed increase, ceruloplasmin
levels during the first 24 hr following injury were found to be significantly reduced in patients
who subsequently developed high ICP. This decrease was found to have prognostic accuracy in
delineating TBI patients based on their ICP status (cutoff of 140 microg/ml; sensitivity: 87%,
specificity: 73%), Likewise, low total serum copper (below 1.32 microg/ml) was also found to be
predictive of high ICP (sensitivity 86%, specificity 73%). These results suggest that initial serum
ceruloplasmin/copper levels may have diagnostic value in predicting patients at risk for
developing high intracranial pressure.
PMID: 20091772 [PubMed - indexed for MEDLINE]
=====================================================================================
Brain. 2010 Feb;133(Pt 2):433-47. Epub 2010 Jan 19.
Quantitative analysis of cellular
inflammation after traumatic spinal cord
injury: evidence for a multiphasic
inflammatory response in the acute to
chronic environment.
Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ.
Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292, USA.
Abstract
Traumatic injury to the central nervous system results in the disruption of the blood brain/spinal
barrier, followed by the invasion of cells and other components of the immune system that can
aggravate injury and affect subsequent repair and regeneration. Although studies of chronic
neuroinflammation in the injured spinal cord of animals are clinically relevant to most patients
living with traumatic injury to the brain or spinal cord, very little is known about chronic
neuroinflammation, though several studies have tested the role of neuroinflammation in the acute
period after injury. The present study characterizes a novel cell preparation method that assesses,
quickly and effectively, the changes in the principal immune cell types by flow cytometry in the
injured spinal cord, daily for the first 10 days and periodically up to 180 days after spinal cord
injury. These data quantitatively demonstrate a novel time-dependent multiphasic response of
cellular inflammation in the spinal cord after spinal cord injury and are verified by quantitative
stereology of immunolabelled spinal cord sections at selected time points. The early phase of
cellular inflammation is comprised principally of neutrophils (peaking 1 day post-injury),
macrophages/microglia (peaking 7 days post-injury) and T cells (peaking 9 days post-injury).
The late phase of cellular inflammation was detected after 14 days post-injury, peaked after 60
days post-injury and remained detectable throughout 180 days post-injury for all three cell types.
Furthermore, the late phase of cellular inflammation (14-180 days post-injury) did not coincide
with either further improvements, or new decrements, in open-field locomotor function after
spinal cord injury. However, blockade of chemoattractant C5a-mediated inflammation after 14
days post-injury reduced locomotor recovery and myelination in the injured spinal cord,
suggesting that the late inflammatory response serves a reparative function. Together, these data
provide new insight into cellular inflammation of spinal cord injury and identify a surprising and
extended multiphasic response of cellular inflammation. Understanding the role of this
multiphasic response in the pathophysiology of spinal cord injury could be critical for the design
and implementation of rational therapeutic treatment strategies, including both cell-based and
pharmacological interventions.
PMID: 20085927 [PubMed - indexed for MEDLINE]PMCID: PMC2858013 [Available on
2011/2/1]
=====================================================================================
Pharmacol Rep. 2009 Nov-Dec;61(6):1163-72.
Study of the cytotoxicity and antioxidant
capacity of N/OFQ(1-13)NH2 and its
structural analogues.
Kirkova M, Zamfirova R, Leśkiewicz M, Kubera M, Lasoń W, Todorov S.
Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev 23, 1113 Sofia,
Bulgaria. [email protected]
Abstract
The effect of side-chain shortening of N/OFQ(1-13)NH(2) at position 9 ([Orn(9)]N/OFQ(113)NH(2), [Dab(9)]N/OFQ(1-13)NH(2), [Dap(9)]N/OFQ(1-13)NH(2)) was studied regarding
potential toxicity and antioxidant capacity. Staurosporine- and H2O2-induced damage of SHSY5Y neuroblastoma cells was not changed in the presence of N/OFQ(1-13)NH(2) and
[Orn(9)]N/OFQ(1-13)NH(2), but was strongly enhanced in the presence of [Dab(9)]N/OFQ(113)NH(2) and [Dap(9)]N/OFQ(1-13)NH(2). Moreover, treatment of cells with the latter two
analogues alone led to cell injury. Neuropeptide-dependent differences in the viability of SHSY5Y cells were also observed, i.e., a cytoprotective effect was observed only in the presence of
N/OFQ(1-13)NH(2) and [Orn(9)]N/OFQ(1-13)NH(2). Compared to [Dab(9)]N/OFQ(113)NH(2) and [Dap(9)]N/OFQ(1-13)NH(2), the effects of N/OFQ(1-13)NH(2) and
[Orn(9)]N/OFQ(1-13)NH(2) were more beneficial in systems generating free oxygen radicals
(O(2)(-) and .OH), as well as on the antioxidant status of rat brain and liver. Taken together, our
findings show that N/OFQ(1-13)NH(2) and its structural analogue [Orn(9)]N/OFQ(1-13)NH(2)
possess more favorable profiles than the other two nociceptin (N/OFQ) analogues. The present
results suggest that shortening of the side-chain of N/OFQ(1-13)NH(2) might increase cell
damage and reduce the viability of SH-SY5Y neuroblastoma cells. Moreover, such alterations
may lead to changes in free-oxygen generating systems and in antioxidant status in animal
tissues.
PMID: 20081252 [PubMed - indexed for MEDLINE]Free Article
=====================================================================================
J Neurochem. 2010 Apr;113(1):131-42. Epub 2010 Jan 12.
Involvement of ERK2 in traumatic spinal
cord injury.
Yu CG, Yezierski RP, Joshi A, Raza K, Li Y, Geddes JW.
Spinal Cord and Brain Injury Research Center and Department of Anatomy and Neurobiology,
University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
[email protected]
Abstract
Activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) are implicated in the
pathophysiology of spinal cord injury (SCI). However, the specific functions of individual ERK
isoforms in neurodegeneration are largely unknown. We investigated the hypothesis that ERK2
activation may contribute to pathological and functional deficits following SCI and that ERK2
knockdown using RNA interference may provide a novel therapeutic strategy for SCI. Lentiviral
ERK2 shRNA and siRNA were utilized to knockdown ERK2 expression in the spinal cord
following SCI. Pre-injury intrathecal administration of ERK2 siRNA significantly reduced
excitotoxic injury-induced activation of ERK2 (p < 0.001) and caspase 3 (p < 0.01) in spinal
cord. Intraspinal administration of lentiviral ERK2 shRNA significantly reduced ERK2
expression in the spinal cord (p < 0.05), but did not alter ERK1 expression. Administration of the
lentiviral ERK2 shRNA vector 1 week prior to severe spinal cord contusion injury resulted in a
significant improvement in locomotor function (p < 0.05), total tissue sparing (p < 0.05), white
matter sparing (p < 0.05), and gray matter sparing (p < 0.05) 6 weeks following severe contusive
SCI. Our results suggest that ERK2 signaling is a novel target associated with the deleterious
consequences of spinal injury.
PMID: 20067580 [PubMed - indexed for MEDLINE]
=====================================================================================
Methods Mol Biol. 2009;566:25-40.
Modeling cerebral ischemia in
neuroproteomics.
Dave JR, Williams AJ, Yao C, Lu XC, Tortella FC.
Department of Applied Neurobiology, Walter Reed Army Institute of Research, Silver Spring,
MD, USA. [email protected]
Abstract
Protein changes induced by traumatic or ischemic brain injury can serve as diagnostic markers as
well as therapeutic targets for neuroprotection. The focus of this chapter is to provide a
representative overview of preclinical brain injury and proteomics analysis protocols for
evaluation and discovery of novel biomarkers. Detailed surgical procedures have been provided
for inducing MCAo and implantation of chronic indwelling cannulas for drug delivery. Sample
collection and tissue processing techniques for collection of blood, CSF, and brain are also
described including standard biochemical methodology for the proteomic analysis of these
tissues.The dynamics of proteomic analysis is a multistep process comprising sample
preparation, separation, quantification, and identification of proteins. Our approach is to separate
proteins first by two-dimensional gel electrophoresis according to charge and molecular mass.
Proteins are then fragmented and analyzed using matrix-assisted laser desorption ionization timeof-flight mass spectrometry (MALDI-TOF MS). Identification of proteins can be achieved by
comparing the mass-to-charge data to protein sequences in respective databases.
PMID: 20058162 [PubMed - indexed for MEDLINE]
=====================================================================================
Oxid Med Cell Longev. 2009 Jan-Mar;2(1):36-42.
Oxidative stress induction of DJ-1 protein in
reactive astrocytes scavenges free radicals
and reduces cell injury.
Yanagida T, Tsushima J, Kitamura Y, Yanagisawa D, Takata K, Shibaike T, Yamamoto A,
Taniguchi T, Yasui H, Taira T, Morikawa S, Inubushi T, Tooyama I, Ariga H.
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Abstract
Astrocytes, one of the predominant types of glial cells, function as both supportive and metabolic
cells for the brain. Under cerebral ischemia/reperfusion-induced oxidative conditions, astrocytes
accumulate and activate in the ischemic region. DJ-1 has recently been shown to be a sensor of
oxidative stress in living cells. However, the function of astrocytic DJ-1 is still unknown. In the
present study, to clarify the effect of astrocytic DJ-1 protein under massive oxidative insult, we
used a focal ischemic rat model that had been subjected to middle cerebral artery occlusion
(MCAO) and reperfusion. We then investigated changes in the distribution of DJ-1 in astrocytes,
DJ-1 release from cultured astrocytes, and the effects of recombinant DJ-1 protein on hydrogen
peroxide (H(2)O(2))-induced death in normal and DJ-1-knockdown SH-SY5Y cells and on in
vitro scavenging of hydroxyl radicals ((*)OH) by electron spin resonance spectrometry. At 24 h
after 2-h MCAO and reperfusion, an infarct lesion was markedly observed using magnetic
resonance imaging and 2,3,5-triphenyltetrazolium chloride staining. In addition, reactive
astrocytes enhanced DJ-1 expression in the penumbral zone of the ischemic core and that DJ-1
protein was extracellularly released from astrocytes by H2O2 in in vitro primary cultures.
Although DJ-1-knockdown SH-SY5Y cells were markedly vulnerable to oxidative stress,
treatment with glutathione S-transferase-tagged recombinant human DJ-1 protein (GST-DJ-1)
significantly inhibited H(2)O(2)-induced cell death. In addition, GST-DJ-1 protein directly
scavenged (*)OH. These results suggest that oxidative stress induces the release of astrocytic DJ1 protein, which may contribute to astrocyte-mediated neuroprotection.
PMID: 20046643 [PubMed - in process]PMCID: PMC2763229Free PMC Article
=====================================================================================
Neuropharmacology. 2010 May;58(6):877-83. Epub 2010 Jan 1.
De-routing neuronal precursors in the adult
brain to sites of injury: role of the
vasculature.
Massouh M, Saghatelyan A.
The Cellular Neurobiology Unit, Centre de Recherche Université Laval Robert-Giffard, Québec,
Québec G1J 2G3, Canada.
Abstract
Neurogenesis in the adult brain occurs predominantly in the two regions, the subventricular zone
(SVZ) bordering the lateral ventricle and subgranular zone (SGZ) of the hippocampus. The
neuronal precursors are produced in the specialized microenvironment called neurovasculature
niche. Recent evidences indicate that in addition to neurogenesis promoting environment,
vasculature also serves as a substrate for migration for these newly generated cells. Importantly,
under some pathological condition, including stroke, neurogenesis is enhanced in the adult brain.
Newly generated neuronal precursors migrate to the sites of injury along the blood vessels and
try to integrate to the damaged brain circuitry. This self-healing capacity of the adult brain is,
however, insufficient to produce a noticeable amelioration in the affected neuronal network since
only a tiny proportion of cells succeed to integrate and survive. Here we review the mechanisms
of neuronal recruitment into the post-stroke regions with particular attention to the guidance of
neuronal precursors along the blood vessels. We also outline some of the molecular factors that
have been used or have a potential to be employed to improve the cell recruitment into the sites
of injury.
Copyright 2010 Elsevier Ltd. All rights reserved.
PMID: 20045706 [PubMed - indexed for MEDLINE]
=====================================================================================
Neurobiol Dis. 2010 Mar;37(3):711-22. Epub 2009 Dec 21.
Ethyl pyruvate protects against hypoxicischemic brain injury via anti-cell death and
anti-inflammatory mechanisms.
Shen H, Hu X, Liu C, Wang S, Zhang W, Gao H, Stetler RA, Gao Y, Chen J.
State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences Fudan
University, Shanghai 200032, China.
Abstract
Ethyl pyruvate (EP) is protective in experimental models of many illnesses. This study
investigates whether EP can protect against neonatal hypoxic-ischemic (H-I) brain injury. Pretreatment with EP significantly reduced brain damage at 7 days post-H-I, with 50 mg/kg EP
achieving over 50% recovery in tissue loss compared to vehicle-treated animals. Delayed
treatment with EP until 30 min after H-I was still neuroprotective. EP-afforded brain protection,
together with neurological function improvement, was observed up to 2 months after H-I. We
further demonstrated an inhibitory effect of EP on cell death, both in an in vivo model of H-I and
in in vitro neuronal cultures subjected to OGD, by reducing calpain activation and calcium
dysregulation. Moreover, EP exerted an anti-inflammatory effect in microglia by inhibiting NFkappaB activation and subsequent release of inflammatory mediators. Taken together, our results
suggest that EP confers potent neuroprotection against neonatal H-I brain injury via its anti-cell
death and anti-inflammatory actions. EP is a potential novel therapeutic agent for neonatal H-I
brain injury.
Published by Elsevier Inc.
PMID: 20026271 [PubMed - indexed for MEDLINE]PMCID: PMC2824008 [Available on
2011/3/1]
=====================================================================================
Mol Cell Proteomics. 2010 May;9(5):963-75. Epub 2009 Dec 17.
Neuroproteomics approaches to decipher
neuronal regeneration and degeneration.
Sun F, Cavalli V.
Department of Anatomy and Neurobiology, Washington University, St. Louis, Missouri 63110,
USA.
Abstract
Given the complexity of brain and nerve tissues, systematic approaches are essential to
understand normal physiological conditions and functional alterations in neurological diseases.
Mass spectrometry-based proteomics is increasingly used in neurosciences to determine both
basic and clinical differential protein expression, protein-protein interactions, and posttranslational modifications. Proteomics approaches are especially useful to understand the
mechanisms of nerve regeneration and degeneration because changes in axons following injury
or in disease states often occur without the contribution of transcriptional events in the cell body.
Indeed, the current understanding of axonal function in health and disease emphasizes the role of
proteolysis, local axonal protein synthesis, and a broad range of post-translational modifications.
Deciphering how axons regenerate and degenerate has thus become a postgenomics problem,
which depends in part on proteomics approaches. This review focuses on recent proteomics
approaches designed to uncover the mechanisms and molecules involved in neuronal
regeneration and degeneration. It emerges that the principal degenerative mechanisms converge
to oxidative stress, dysfunctions of axonal transport, mitochondria, chaperones, and the
ubiquitin-proteasome systems. The mechanisms regulating nerve regeneration also impinge on
axonal transport, cytoskeleton, and chaperones in addition to changes in signaling pathways. We
also discuss the major challenges to proteomics work in the nervous system given the complex
organization of the brain and nerve tissue at the anatomical, cellular, and subcellular levels.
PMID: 20019051 [PubMed - indexed for MEDLINE]PMCID: PMC2871427 [Available on
2011/5/1]
=====================================================================================
Hippocampus. 2009 Dec 15. [Epub ahead of print]
Phosphacan and receptor protein tyrosine
phosphatase β expression mediates
deafferentation-induced synaptogenesis.
Harris JL, Reeves TM, Phillips LL.
Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth
University Medical Center, Richmond, Virginia.
Abstract
This study documents the spatial and temporal expression of three structurally related
chondroitin sulfated proteoglycans (CSPGs) during synaptic regeneration induced by brain
injury. Using the unilateral entorhinal cortex (EC) lesion model of adaptive synaptogenesis, we
documented mRNA and protein profiles of phosphacan and its two splice variants, full length
receptor protein tyrosine phosphatase β (RPTPβ) and the short transmembrane receptor form
(sRPTPβ), at 2, 7, and 15 days postlesion. We report that whole hippocampal sRPTPβ protein
and mRNA are persistently elevated over the first two weeks after UEC. As predicted, this
transmembrane family member was localized adjacent to synaptic sites in the deafferented
neuropil and showed increased distribution over that zone following lesion. By contrast, whole
hippocampal phosphacan protein was not elevated with deafferentation; however, its mRNA was
increased during the period of sprouting and synapse formation (7d). When the zone of synaptic
reorganization was sampled using molecular layer/granule cell (ML/GCL) enriched dissections,
we observed an increase in phosphacan protein at 7d, concurrent with the observed hippocampal
mRNA elevation. Immunohistochemistry also showed a shift in phosphacan distribution from
granule cell bodies to the deafferented ML at 2 and 7d postlesion. Phosphacan and sRPTPβ were
not colocalized with glial fibrillary acid protein (GFAP), suggesting that reactive astrocytes were
not a major source of either proteoglycan. While transcript for the developmentally prominent
full length RPTPβ was also increased at 2 and 15d, its protein was not detected in our adult
samples. These results indicate that phosphacan and RPTPβ splice variants participate in both the
acute degenerative and long-term regenerative phases of reactive synaptogenesis. These results
suggest that increase in the transmembrane sRPTPβ tyrosine phosphatase activity is critical to
this plasticity, and that local elevation of extracellular phosphacan influences dendritic
organization during synaptogenesis. © 2009 Wiley-Liss, Inc.
PMID: 20014386 [PubMed - as supplied by publisher]PMCID: PMC2889017 [Available on
2011/6/1]
=====================================================================================
J Cereb Blood Flow Metab. 2010 Apr;30(4):744-56. Epub 2009 Dec 16.
Ischemic preconditioning regulates
expression of microRNAs and a predicted
target, MeCP2, in mouse cortex.
Lusardi TA, Farr CD, Faulkner CL, Pignataro G, Yang T, Lan J, Simon RP, Saugstad JA.
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Abstract
Preconditioning describes the ischemic stimulus that triggers an endogenous, neuroprotective
response that protects the brain during a subsequent severe ischemic injury, a phenomenon
known as 'tolerance'. Ischemic tolerance requires new protein synthesis, leads to genomic
reprogramming of the brain's response to subsequent ischemia, and is transient. MicroRNAs
(miRNAs) regulate posttranscriptional gene expression by exerting direct effects on messenger
RNA (mRNA) translation. We examined miRNA expression in mouse cortex in response to
preconditioning, ischemic injury, and tolerance. The results of our microarray analysis revealed
that miRNA expression is consistently altered within each group, but that preconditioning was
the foremost regulator of miRNAs. Our bioinformatic analysis results predicted that
preconditioning-regulated miRNAs most prominently target mRNAs that encode transcriptional
regulators; methyl-CpG binding protein 2 (MeCP2) was the most prominent target. No studies
have linked MeCP2 to preconditioning or tolerance, yet miR-132, which regulates MeCP2
expression, is decreased in preconditioned cortex. Downregulation of miR-132 is consistent with
our finding that preconditioning ischemia induces a rapid increase in MeCP2 protein, but not
mRNA, in mouse cortex. These studies reveal that ischemic preconditioning regulates expression
of miRNAs and their predicted targets in mouse brain cortex, and further suggest that miRNAs
and MeCP2 could serve as effectors of ischemic preconditioning-induced tolerance.
PMID: 20010955 [PubMed - indexed for MEDLINE]PMCID: PMC2935903Free PMC Article
=====================================================================================
Stem Cells. 2010 Feb;28(2):297-307.
Beta-catenin signaling increases in
proliferating NG2+ progenitors and
astrocytes during post-traumatic gliogenesis
in the adult brain.
White BD, Nathe RJ, Maris DO, Nguyen NK, Goodson JM, Moon RT, Horner PJ.
Program in Neurobiology and Behavior, University of Washington School of Medicine and
Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109, USA.
Abstract
Wnt/beta-catenin signaling can influence the proliferation and differentiation of progenitor
populations in the hippocampus and subventricular zone, known germinal centers in the adult
mouse brain. It is not known whether beta-catenin signaling occurs in quiescent glial progenitors
in cortex or spinal cord, nor is it known whether beta-catenin is involved in the activation of glial
progenitor populations after injury. Using a beta-catenin reporter mouse (BATGAL mouse), we
show that beta-catenin signaling occurs in NG2 chondroitin sulfate proteoglycan+ (NG2)
progenitors in the cortex, in subcallosal zone (SCZ) progenitors, and in subependymal cells
surrounding the central canal. Interestingly, cells with beta-catenin signaling increased in the
cortex and SCZ following traumatic brain injury (TBI) but did not following spinal cord injury.
Initially after TBI, beta-catenin signaling was predominantly increased in a subset of NG2+
progenitors in the cortex. One week following injury, the majority of beta-catenin signaling
appeared in reactive astrocytes but not oligodendrocytes. Bromodeoxyuridine (BrdU) paradigms
and Ki-67 staining showed that the increase in beta-catenin signaling occurred in newly born
cells and was sustained after cell division. Dividing cells with beta-catenin signaling were
initially NG2+; however, by four days after a single injection of BrdU, they were predominantly
astrocytes. Infusing animals with the mitotic inhibitor cytosine arabinoside prevented the
increase of beta-catenin signaling in the cortex, confirming that the majority of beta-catenin
signaling after TBI occurs in newly born cells. These data argue for manipulating the Wnt/betacatenin pathway after TBI as a way to modify post-traumatic gliogenesis.
PMID: 19960516 [PubMed - indexed for MEDLINE]
=====================================================================================
Acta Neurochir Suppl. 2010;106:307-10.
Serine protease inhibitor attenuates
intracerebral hemorrhage-induced brain
injury and edema formation in rat.
Nakamura T, Kuroda Y, Hosomi N, Okabe N, Kawai N, Tamiya T, Xi G, Keep RF, Itano T.
Department of Neurobiology and Neurological Surgery, Kagawa University Faculty of
Medicine, Kita, Kagawa, Japan. [email protected]
Abstract
Our previous studies have demonstrated that thrombin plays an important role in intracerebral
hemorrhage (ICH)-induced brain injury and edema formation. We, therefore, examined whether
nafamostat mesilate (FUT), a serine protease inhibitor, can reduce ICH-induced brain injury.
Anesthetized male Sprague-Dawley rats received an infusion of autologous whole blood (100
microL), thrombin (5U/50 microL) or type VII collagenase (0.4 U/2 microL) into the right basal
ganglia, the three ICH models used in the present study. FUT (10 mg/kg) or vehicle was
administered intraperitoneally 6 h after ICH (or immediately after thrombin infusion) and then at
12-h intervals (six treatments in total, n = 5 in each group). All rats were sacrificed 72 h later.
We also examined whether FUT promotes rebleeding in a model in which ICH was induced by
intracerebral injection of collagenase. Systemic administration of FUT starting 6 h after ICH
reduced brain water content in the ipsilateral basal ganglia 72 h after ICH compared with vehicle.
FUT attenuated ICH-induced changes in 8-OHdG and thrombin-reduced brain edema. FUT did
not increase collagenase-induced hematoma volume. FUT attenuates ICH-induced brain edema
and DNA injury suggesting that serine protease inhibitor may be potential therapeutic agent for
ICH.
PMID: 19812969 [PubMed - indexed for MEDLINE]
=====================================================================================
Dev Neurorehabil. 2009;12(5):255-68.
Hitting a moving target: Basic mechanisms of
recovery from acquired developmental brain
injury.
Giza CC, Kolb B, Harris NG, Asarnow RF, Prins ML.
Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles,
California 90095, USA. [email protected]
Abstract
Acquired brain injuries represent a major cause of disability in the pediatric population.
Understanding responses to developmental acquired brain injuries requires knowledge of the
neurobiology of normal development, age-at-injury effects and experience-dependent
neuroplasticity. In the developing brain, full recovery cannot be considered as a return to the
premorbid baseline, since ongoing maturation means that cerebral functioning in normal
individuals will continue to advance. Thus, the recovering immature brain has to 'hit a moving
target' to achieve full functional recovery, defined as parity with age-matched uninjured peers.
This review will discuss the consequences of developmental injuries such as focal lesions,
diffuse hypoxia and traumatic brain injury (TBI). Underlying cellular and physiological
mechanisms relevant to age-at-injury effects will be described in considerable detail, including
but not limited to alterations in neurotransmission, connectivity/network functioning, the
extracellular matrix, response to oxidative stress and changes in cerebral metabolism. Finally,
mechanisms of experience-dependent plasticity will be reviewed in conjunction with their effects
on neural repair and recovery.
PMID: 19956795 [PubMed - indexed for MEDLINE]PMCID: PMC2772114Free PMC Article
=====================================================================================
J Vis Exp. 2009 Nov 20;(33). pii: 1324. doi: 10.3791/1324.
Combining peripheral nerve grafting and
matrix modulation to repair the injured rat
spinal cord.
Houle JD, Amin A, Cote MP, Lemay M, Miller K, Sandrow H, Santi L, Shumsky J, Tom V.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, USA.
[email protected]
Abstract
Traumatic injury to the spinal cord (SCI) causes death of neurons, disruption of motor and
sensory nerve fiber (axon) pathways and disruption of communication with the brain. One of the
goals of our research is to promote axon regeneration to restore connectivity across the lesion
site. To accomplish this we developed a peripheral nerve (PN) grafting technique where
segments of sciatic nerve are either placed directly between the damaged ends of the spinal cord
or are used to form a bridge across the lesion. There are several advantages to this approach
compared to transplantation of other neural tissues; regenerating axons can be directed towards a
specific target area, the number and source of regenerating axons is easily determined by tracing
techniques, the graft can be used for electrophysiological experiments to measure functional
recovery associated with axons in the graft, and it is possible to use an autologous nerve to
reduce the possibility of graft rejection. In our lab we have performed both autologous (donor
and recipient are the same animal) and heterologous (donor and recipient are different animals)
grafts with comparable results. This approach has been used successfully in both acute and
chronic injury situations. Regenerated axons that reach the distal end of the PN graft often fail to
extend back into the spinal cord, so we use microinjections of chondroitinase to degrade
inhibitory molecules associated with the scar tissue surrounding the area of SCI. At the same
time we have found that providing exogenous growth and trophic molecules encourages longer
distance axonal regrowth into the spinal cord. Several months after transplantation we perform a
variety of anatomical, behavioral and electrophysiological tests to evaluate the recovery of
function in our spinal cord injured animals. This experimental approach has been used
successfully in several spinal cord injury models, at different levels of injury and in different
species (mouse, rat and cat). Importantly, the peripheral nerve grafting approach is effective in
promoting regeneration by acute and chronically injured neurons.
PMID: 19935638 [PubMed - indexed for MEDLINE]
=====================================================================================
Mol Cell Neurosci. 2010 Feb;43(2):201-8. Epub 2009 Nov 11.
Fasudil, a Rho kinase inhibitor, drives
mobilization of adult neural stem cells after
hypoxia/reoxygenation injury in mice.
Ding J, Li QY, Yu JZ, Wang X, Sun CH, Lu CZ, Xiao BG.
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory
of Medical Neurobiology, Fudan University, Shanghai, China.
Abstract
Rho kinase (ROCK) is important in fundamental processes of cell proliferation and survival.
Blockade of ROCK promotes stem cell survival in vitro and axonal regeneration in vivo,
exhibiting therapeutic potential such as spinal cord injuries and stroke. Here, we used the model
of hypoxia/reoxygenation (H/R) injury to explore the possibility whether Fasudil, a ROCK
inhibitor in clinical application for subarachnoid hemorrhage and stroke, mobilizes adult neural
stem cells in vivo. Most interestingly, Fasudil triggers neurogenesis especially in the
subventricular zone after H/R. The increase of Brdu+ cholinergic neurons was observed in
striatum and forebrain cortex of Fasudil-treated mice after 30 days. Further observation
demonstrates that both levels of granulocyte colony-stimulating factor (G-CSF) and astrocytes
expressing G-CSF were elevated in mice treated with Fasudil, as compared to mice injected with
saline. In vitro H/R model of cultured astrocytes, Fasudil promoted astrocytes to produce G-CSF
in a dose-dependent manner. In addition, antibody neutralization and receptor blocking of the GCSF pathway clearly demonstrate that Fasudil-induced neurogenesis was mediated partially
through astrocyte-derived G-CSF. Our results indicate that Fasudil might represent a promising
therapeutic perspective by mobilizating endogenous adult neural stem cells in the CNS.
Copyright 2009 Elsevier Inc. All rights reserved.
PMID: 19913617 [PubMed - indexed for MEDLINE]
=====================================================================================
Stem Cells. 2010 Jan;28(1):127-39.
Transplantation of embryonic neural
stem/precursor cells overexpressing
BM88/Cend1 enhances the generation of
neuronal cells in the injured mouse cortex.
Makri G, Lavdas AA, Katsimpardi L, Charneau P, Thomaidou D, Matsas R.
Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, 11521 Athens,
Greece.
Abstract
The intrinsic inability of the central nervous system to efficiently repair traumatic injuries
renders transplantation of neural stem/precursor cells (NPCs) a promising approach towards
repair of brain lesions. In this study, NPCs derived from embryonic day 14.5 mouse cortex were
genetically modified via transduction with a lentiviral vector to overexpress the neuronal lineagespecific regulator BM88/Cend1 that coordinates cell cycle exit and differentiation of neuronal
precursors. BM88/Cend1-overexpressing NPCs exhibiting enhanced differentiation into neurons
in vitro were transplanted in a mouse model of acute cortical injury and analyzed in comparison
with control NPCs. Immunohistochemical analysis revealed that a smaller proportion of
BM88/Cend1-overexpressing NPCs, as compared with control NPCs, expressed the neural stem
cell marker nestin 1 day after transplantation, while the percentage of nestin-positive cells was
significantly reduced thereafter in both types of cells, being almost extinct 1 week post-grafting.
Both types of cells did not proliferate up to 4 weeks in vivo, thus minimizing the risk of
tumorigenesis. In comparison with control NPCs, Cend1-overexpressing NPCs generated more
neurons and less glial cells 1 month after transplantation in the lesioned cortex whereas the
majority of graft-derived neurons were identified as GABAergic interneurons. Furthermore,
transplantation of Cend1-overexpressing NPCs resulted in a marked reduction of astrogliosis
around the lesioned area as compared to grafts of control NPCs. Our results suggest that
transplantation of Cend1-overexpressing NPCs exerts beneficial effects on tissue regeneration by
enhancing the number of generated neurons and restricting the formation of astroglial scar, in a
mouse model of cortical brain injury.
PMID: 19911428 [PubMed - indexed for MEDLINE]
=====================================================================================
Stroke. 2010 Jan;41(1):166-72. Epub 2009 Nov 12.
Neuroprotection against hypoxic-ischemic
brain injury by inhibiting the apoptotic
protease activating factor-1 pathway.
Gao Y, Liang W, Hu X, Zhang W, Stetler RA, Vosler P, Cao G, Chen J.
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
[email protected]
Abstract
BACKGROUND AND PURPOSE: Emerging evidence suggests that mitochondrial damagemediated neuronal apoptosis is a major contributor to neonatal hypoxic-ischemic (H-I) brain
injury. This study was performed to determine whether targeted inhibition of the apoptotic
protease activating factor-1 (Apaf-1) signaling pathway downstream of mitochondrial damage
confers neuroprotection in rodent models of neonatal H-I.
METHODS: H-I was induced in 7-day-old (P7) transgenic mice overexpressing the specific
Apaf-1-inhibitory protein AIP. Apaf-1 inhibition was also achieved in P7 rats by protein
transduction-enhanced delivery of recombinant AIP. Pups were euthanized 6 to 24 hours after HI for assessing caspase activation and mitochondrial release of cytochrome c and AIF, and 7 days
after H-I for analyzing brain tissue damage. Sensorimotor functions were assessed in rats up to 4
weeks after H-I.
RESULTS: Transgenic overexpression of AIP protected against H-I brain injury, resulting in
attenuated activation of caspase-9 and caspase-3, and attenuated brain tissue loss. In neonatal H-I
rats, intraperitoneal injection of TAT-AIP, but not the control proteins TAT-GFP or AIP,
decreased caspase activation and brain damage and improved neurological functions.
Neuroprotection conferred by AIP was also associated with significantly reduced release of
cytochrome c and AIF from mitochondria.
CONCLUSIONS: The Apaf-1 signaling pathway, which transmits cell death signals after
mitochondrial damage to effector caspases, may be a legitimate therapeutic target for the
treatment of neonatal H-I brain injury.
PMID: 19910549 [PubMed - indexed for MEDLINE]PMCID: PMC2799533 [Available on
2011/1/1]
=====================================================================================
Neuroscience. 2010 Feb 3;165(3):863-73. Epub 2009 Nov 10.
Group II metabotropic glutamate receptor
activation by agonist LY379268 treatment
increases the expression of brain derived
neurotrophic factor in the mouse brain.
Di Liberto V, Bonomo A, Frinchi M, Belluardo N, Mudò G.
Department of Experimental Medicine, Division of Human Physiology, Laboratory of Molecular
Neurobiology, University of Palermo, Corso Tukory 129, 90134 Palermo, Italy.
Abstract
A number of in vitro and in vivo studies using selective agonists have indicated a
neuroprotective role for group-II metabotropic glutamate (mGlu2/3) receptors in various models
of neuronal injury. Although an interplay among neurotrophic factors and mGlu2/3 receptors
signalling system has been suggested as possible mechanism involved on neuroprotection, at
present poor information are available concerning the in vivo regulation by mGlu2/3 receptors
activation of specific neurotrophic factors. By using in situ hybridization and western blotting
methods the aim of present study was to analyse the potential regulatory role of selective
mGluR2/3 agonist LY379268 treatment on brain derived neurotrophic factor (BDNF) expression
in the mouse brain. The treatment with LY379268 evidenced a significant upregulation of BDNF
mRNA levels in the cerebral cortex and in the hippocampal formation with a peak at 3 h from
treatment and its disappearance already at 6 h from treatment. An analysis of dose-effect curve
revealed that LY379268 may significantly enhance BDNF mRNA expression already at dose of
0.250 mg/kg b.w. The upregulation of BDNF mRNA expression was followed by a significant
increase of BDNF protein levels at 24 h from LY379268 treatment. These effects of LY379268
treatment on BDNF expression were restricted to neuronal cells and were blocked by the new
selective mGlu2/3 receptor antagonist LY341495, suggesting a receptor specificity. Taken
together these findings suggest that several previous observed neuroprotective and trophic
actions of mGluR2/3 agonists treatment may be mediated, at least in the cerebral cortex and
hippocampal formation, by upregulation of BDNF expression.
Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
PMID: 19909793 [PubMed - indexed for MEDLINE]
=====================================================================================
J Neurosci Res. 2010 May 1;88(6):1182-92.
Promoting directional axon growth from
neural progenitors grafted into the injured
spinal cord.
Bonner JF, Blesch A, Neuhuber B, Fischer I.
Department of Neurobiology and Anatomy, Drexel University College of Medicine,
Philadelphia, Pennsylvania.
Abstract
Spinal cord injury (SCI) is a devastating condition characterized by disruption of axonal
connections, failure of axonal regeneration, and loss of motor and sensory function. The
therapeutic promise of neural stem cells has been focused on cell replacement, but many
obstacles remain in obtaining neuronal integration following transplantation into the injured
CNS. This study investigated the neurotransmitter identity and axonal growth potential of neural
progenitors following grafting into adult rats with a dorsal column lesion. We found that using a
combination of neuronal and glial restricted progenitors (NRP and GRP) produced graft-derived
glutamatergic and GABAergic neurons within the injury site, with minimal axonal extension.
Administration of brain-derived neurotrophic factor (BDNF) with the graft promoted modest
axonal growth from grafted cells. In contrast, injecting a lentiviral vector expressing BDNF
rostral into the injured area generated a neurotrophin gradient and promoted directional growth
of axons for up to 9 mm. Animals injected with BDNF lentivirus (at 2.5 and 5.0 mm) showed
significantly more axons and significantly longer axons than control animals injected with GFP
lentivirus. However, only the 5.0-mm-BDNF group showed a preference for extension in the
rostral direction. We concluded that NRP/GRP grafts can be used to produce excitatory and
inhibitory neurons, and neurotrophin gradients can guide axonal growth from graft-derived
neurons toward putative targets. Together they can serve as a building block for neuronal cell
replacement of local circuits and formation of neuronal relays.
(c) 2009 Wiley-Liss, Inc.
PMID: 19908250 [PubMed - indexed for MEDLINE]PMCID: PMC2844860 [Available on
2011/5/1]
=====================================================================================
J Cereb Blood Flow Metab. 2010 Mar;30(3):628-37. Epub 2009 Nov 11.
The adverse pial arteriolar and axonal
consequences of traumatic brain injury
complicated by hypoxia and their therapeutic
modulation with hypothermia in rat.
Gao G, Oda Y, Wei EP, Povlishock JT.
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center,
Richmond, Virginia 23298, USA.
Abstract
This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and
axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats
were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess
vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to
amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone,
IAI and hypoxia, IAI and hypoxia before induction of moderate hypothermia (33 degrees C), IAI
and hypoxia induced during hypothermic intervention, and IAI and hypoxia initiated after
hypothermia. Hypoxia alone had no impact on vascular reactivity or axonal damage.
Acceleration injury and posttraumatic hypoxia resulted in dramatic axonal damage and altered
vascular reactivity. When IAI and hypoxia were followed by hypothermic intervention, no
axonal or vascular protection ensued. However, when IAI was followed by hypoxia induced
during hypothermia, axonal and vascular protection followed. When this same hypoxic insult
followed the use of hypothermia, no benefit ensued. These studies show that early hypoxia and
delayed hypoxia exert damaging axonal and vascular consequences. Although this damage is
attenuated by hypothermia, this follows only when hypoxia occurs during hypothermia, with no
benefit found if the hypoxic insult proceeds or follows hypothermia.
PMID: 19904286 [PubMed - indexed for MEDLINE]
=====================================================================================
J Neurosci. 2009 Nov 4;29(44):13823-36.
Estrogen attenuates ischemic oxidative
damage via an estrogen receptor alphamediated inhibition of NADPH oxidase
activation.
Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, Vadlamudi RK, Brann DW.
Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, and
Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Abstract
The goal of this study was to elucidate the mechanisms of 17beta-estradiol (E(2)) antioxidant and
neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated
antioxidant mechanism for E(2) during stroke, as well as a hypersensitivity of the CA3/CA4
region to ischemic injury after prolonged hypoestrogenicity. E(2) neuroprotection was shown to
involve a profound attenuation of NADPH oxidase activation and superoxide production in
hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen
receptor alpha (ERalpha)-mediated nongenomic signaling, involving Akt activation and
subsequent phosphorylation/inactivation of Rac1, a factor critical for activation of NOX2
NADPH oxidase. Intriguingly, E(2) nongenomic signaling, antioxidant action, and
neuroprotection in the CA1 region were lost after long-term E(2) deprivation, and this loss was
tissue specific because the uterus remained responsive to E(2). Correspondingly, a remarkable
loss of ERalpha, but not ERbeta, was observed in the CA1 after long-term E(2) deprivation, with
no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated
antioxidant mechanism in neurons by E(2) provides support and mechanistic insights for a
"critical period" of E(2) replacement in the hippocampus and demonstrates a heretofore unknown
hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.
PMID: 19889994 [PubMed - indexed for MEDLINE]PMCID: PMC2807671Free PMC Article
=====================================================================================
J Neurotrauma. 2009 Nov;26(11):1987-97.
Human amnion-derived multipotent
progenitor cell treatment alleviates traumatic
brain injury-induced axonal degeneration.
Chen Z, Tortella FC, Dave JR, Marshall VS, Clarke DL, Sing G, Du F, Lu XC.
Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed
Army Institute of Research, Silver Spring, Maryland 20910, USA.
[email protected]
Abstract
To identify a viable cell source with potential neuroprotective effects, we studied amnionderived multipotent progenitor (AMP) cells in a rat model of penetrating ballistic-like brain
injury (PBBI). AMP cells were labeled with fluorescent dye PKH26 and injected in rats
immediately following right hemispheric PBBI or sham PBBI surgery by ipsilateral i.c.v.
administration. At 2 weeks post-injury, severe necrosis developed along the PBBI tract and
axonal degeneration was prominent along the corpus callosum (cc) and in the ipsilateral
thalamus. Injected AMP cells first entered the subventricular zone (SVZ) in both sham and PBBI
rats. Further AMP cell migration along the cc only occurred in PBBI animals. No significant
difference in injury volume was observed across all treatment groups. In contrast, treatment with
AMP cells significantly attenuated axonal degeneration in both the thalamus and the cc.
Interestingly, PKH26-labeled AMP cells were detected only in the SVZ and the cc (in parallel
with the axonal degeneration), but not in the thalamus. None of the labeled AMP cells appeared
to express neural differentiation, as evidenced by the lack of double labeling with nestin, S-100,
GFAP, and MAP-2 immunostaining. In conclusion, AMP cell migration was specifically induced
by PBBI and requires SVZ homing, yet the neuroprotective effect of intracerebral ventrical
treatment using AMP cells was not limited to the area where the cells were present. This
suggests that the attenuation of the secondary brain injury following PBBI was likely to be
mediated by mechanisms other than cell replacement, possibly through delivery or sustained
secretion of neurotrophic factors.
PMID: 19886807 [PubMed - indexed for MEDLINE]
=====================================================================================
Prog Neurobiol. 2010 Feb 9;90(2):256-62. Epub 2009 Oct 21.
Connection between inflammatory processes
and transmittor function-Modulatory effects
of interleukin-1.
Spulber S, Schultzberg M.
Department of Neurobiology, Care Sciences and Society, Division of Neurodegeneration,
Karolinska Institutet, SE-141 86 Stockholm, Sweden.
Abstract
Cells in the nervous system can respond to different kinds of stress, e.g. injury, with production
and release of inflammatory molecules, including cytokines. One of the most important
proinflammatory cytokines is interleukin-1, affecting most organs of the body. The high
constitutive expression of interleukin-1 in the adrenal gland provides a source for local and
systemic actions, in addition to activated monocytes. In the brain, the constitutive expression is
low, but activated microglia produce and release interleukin-1 during pathological conditions
such as neurodegenerative disorders (e.g. stroke, traumatic brain injury, Alzheimer's disease,
Parkinson's disease). Interleukin-1 has an important role in mediating 'sickness symptoms' such
as fever, in response to infections. Its role in neurodegeneration is not fully elucidated, but there
is evidence for involvement in both amyloidosis and tau pathology, major neuropathological
hallmarks of Alzheimer's disease. The interleukin-1 family at present consists of 11 members,
one of which is the endogenous receptor antagonist. Overexpression of this antagonist in the
CNS in a transgenic mouse strain, Tg hsIL-1ra, has allowed studies on morphological and
functional effects of blocking interleukin-1 receptor-mediated activity in the brain. Marked
alterations of brain morphology such as reduced hippocampal and cortical volume correlate with
behavioural deficits. Decreased anxiety and impaired long-term memory are among the
consequences. Intact interleukin-1 signalling is important for the brain's ability to adapt to acute
and chronic neuroinflammation. Increased amplitude and prolongation of proinflammatory
cytokine production underly the behavioural alterations characteristic for ageing. Moreover,
deregulated expression of interleukin-1 is associated with ageing-related chronic
neurodegenerative disorders.
Copyright 2009 Elsevier Ltd. All rights reserved.
PMID: 19853010 [PubMed - indexed for MEDLINE]
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Brain Res. 2009 Nov 17;1298:24-36. Epub 2009 Sep 1.
Identification of calcium sensing receptor
(CaSR) mRNA-expressing cells in normal
and injured rat brain.
Mudò G, Trovato-Salinaro A, Barresi V, Belluardo N, Condorelli DF.
Department of Experimental Medicine, Division of Human Physiology, Laboratory of Molecular
Neurobiology, University of Palermo, corso Tukory 129, Palermo, Italy. [email protected]
Abstract
Calcium sensing receptor (CaSR), isolated for the first time from bovine and human parathyroid,
is a G-protein-coupled receptors that has been involved in diverse physiological functions. At
present a complete in vivo work on the identification of CaSR mRNA-expressing cells in the
adult brain lacks and this investigation was undertaken in order to acquire more information on
cell type expressing CaSR mRNA in the rat brain and to analyse for the first time its expression
in different experimental models of brain injury. The expression of CaSR mRNAs was found
mainly in scattered cells throughout almost all the brain regions. A double labeling analysis
showed a colocalization of CaSR mRNA expression in neurons and oligodendrocytes, whereas it
was not found expressed both in the microglia and in astrocytes. One week after kainate-induced
seizure CaSR was found in the injured CA3 region of the hippocampus and very interestingly it
was found up-regulated in the neurons of CA1-CA2 and dentate gyrus. Similarly, 1 week
following ibotenic acid injection in the hippocampus, CaSR mRNA expression was increased in
oligodendrocytes both in the lesioned area and in the contralateral CA1-CA3 pyramidal cell
layers and dentate gyrus. One week after needle-induced mechanical lesion an increase of
labeled cells expressing CaSR mRNA was observed along the needle track. In conclusion, the
present results contribute to extend available data on cell type-expressing CaSR in normal and
injured brain and could spur to understand the role of CaSR in repairing processes of brain
injury.
PMID: 19728995 [PubMed - indexed for MEDLINE]
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Commun Integr Biol. 2009 Jul;2(4):318-20.
Internal regulation of neurite plasticity: A
general model.
Mingorance-Le Meur A.
Department of Cellular and Physiological Sciences; The University of British Columbia; and
ICORD; Vancouver, BC CA.
Abstract
The mature central nervous system has a very limited capacity to repair itself after injury or
disease, often leading to lifelong disabilities. Two key questions in neurobiology are why the
brain has such limited plasticity, and how we could enhance it. There has been extensive
research on how external inhibitors, present in the mature central nervous system, cooperate to
restrict neurite plasticity-the ability of neurons to sprout and reorganize their connections. In a
recent article, we have described an unsuspected mechanism by which neurons control (and
actually repress) their capacity to sprout in a cell-autonomous manner. Our discovery implies
that protrusive potential is not lost in mature neurons but internally repressed. This discovery
opens up new research avenues and has a strong potential from a translational standpoint. Here I
review our previous results and propose a more general hypothesis on the molecular mechanisms
controlling neurite plasticity.
PMID: 19721877 [PubMed - in process]PMCID: PMC2734034Free PMC Article
=====================================================================
================Neurosci Lett. 2009 Nov 20;465(3):220-5. Epub 2009 Aug 22.
Adenovirus-mediated brain-derived
neurotrophic factor expression regulated by
hypoxia response element protects brain
from injury of transient middle cerebral
artery occlusion in mice.
Shi Q, Zhang P, Zhang J, Chen X, Lu H, Tian Y, Parker TL, Liu Y.
The Institute of Neurobiology, Enviroment and Genes Related to Diseases Key laboratory of
Education Ministry, the State Key Subject for Physiology, Xi'an Jiaotong University College of
Medicine, Xi'an, Shaanxi, 710061, PR China.
Abstract
Some gene expression may be regulated by hypoxia-responsive element (HRE) that is bound by
hypoxia-inducible factor-1 (HIF-1) which is up-regulated during cerebral ischemia. To explore
ischemia/hypoxia-controlled expression and the neuroprotective effects of brain-derived
neurotrophic factor (BDNF) after ischemic brain injury, an adenoviral vector using five copies of
hypoxia response element (HRE) in the vascular endothelial growth factor gene to regulate the
expression of BDNF gene (Ad5HRE:BDNF) was constructed, and its efficacy was verified for
driving BDNF expression in cultured Hela cells under hypoxic condition by ELISA. We found
that the concentration of BDNF in the Ad5HRE:BDNF-transfected culture media was 28-fold
greater in a hypoxic condition than under normoxia. To examine the effect of Ad5HRE:BDNF
on ischemic brain injury in vivo, Ad5HRE:BDNF was injected into right caudate putamen of
adult mice 7 days prior to 60 min transient middle cerebral artery occlusion (MCAO). It was
found that exogenous BDNF expression was increased in the Ad5HRE-BDNF-treated group and
infarct volume of the Ad5HRE:BDNF-treated group at 3 days after MCAO was significantly
smaller than that of vehicle- or AdNull-treated groups. Moreover, Ad5HRE:BDNF injection
resulted in significantly improved sensorimotor scores 7 days after MCAO and induced a
reduction in the number of Fluoro-Jade B-positive neurons and TUNEL-positive cells, compared
with vehicle- or AdNull-injection. Our findings suggest that BDNF expression could be
regulated in hypoxia/ischemia condition with five copies of HRE and ameliorates ischemic brain
injury in a mouse focal cerebral ischemia model.
PMID: 19703519 [PubMed - indexed for MEDLINE]
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Cell Stem Cell. 2009 Aug 7;5(2):178-90.
The death receptor CD95 activates adult
neural stem cells for working memory
formation and brain repair.
Corsini NS, Sancho-Martinez I, Laudenklos S, Glagow D, Kumar S, Letellier E, Koch P,
Teodorczyk M, Kleber S, Klussmann S, Wiestler B, Brüstle O, Mueller W, Gieffers C, Hill O,
Thiemann M, Seedorf M, Gretz N, Sprengel R, Celikel T, Martin-Villalba A.
Molecular Neurobiology, German Cancer Research Center, Heidelberg, Germany.
Comment in:

Cell Stem Cell. 2009 Aug 7;5(2):128-30.
Abstract
Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced
upon central nervous system injury. However, the final contribution of newborn neurons to
neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death
receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival
and neuronal specification. These effects are mediated via activation of the
Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein
translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1
region, in the naive dentate gyrus, and after forced expression of CD95L in the adult
subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and
working memory deficits. Following global ischemia, CD95-mediated brain repair rescued
behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for
ongoing and injury-induced neurogenesis.
PMID: 19664992 [PubMed - indexed for MEDLINE]
Neurotransmitter Alterations in a Model
. of Yerinatal Hypoxrc-lschemc Bran
r-
1
TT.T1*
n
T.
injury Michael V. Johnston, MD
http://deepblue.lib.umich.edu/bitstream/2027.42/50300/1/410130507_ftp.pdf