Download PowerPoint Presentation - Society for Neuroscience San Diego 2001

Society for Neuroscience
San Diego 2001
A Personal Summary
Wise Young, Ph.D., M.D.
Major Impressions
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Everybody and their uncles are doing gene
chips with their little lists of genes
Nuclear transcription factors that control
differentiation are hot (too hot)
Therapeutic vaccines are proliferating
Very few or now studies are assessing
treatments of chronic spinal cord injury
Injury studies are becoming very popular
Exciting Advances
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Astrocytes can produce neurons
Radial glial cells are neural stem cells
C3 blockade of Rho stimulates regeneration
AIT-082 stimulates neurotrophin & stem cells
L2 CPG stimulation improves walking efficiency
Enteric glia stimulate regeneration of spinal roots
Noxious experience reduce BBB scores
Nogo receptor blockade causes regeneration
Minocycline remarkably improves BBB scores when
given 0-24 hours after spinal cord contusion
Astrocytes Produce Neurons
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Stem cells in the SVZ are probably astrocytes
– Alvarez-Buylla, et al. reported that subventricular
zone (SVZ) stem cells are astrocytes that give rise
to neurons.
• They used ARA-C drip to stop cell proliferation of stem
cells. When the ARA-C stopped, production of neurons
restarted. Astrocyte-like cells adjacent to ventricular
ependymal cells generated cells that became neurons
• GFAP-promoter linked Avian virus receptor expression
transgenic mouse allowed specific labelling of astrocytes.
The labeled cells started as astrocytes and then
produced neurons in the olfactory bulb and the
hippocampus.
Radial Glial Stem Cells
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Noctor, et al. at Columbia
– retrovirus infected radial glial cells
transform to become adult neurons that
show all the characteristics of neurons
– In avian studies, radial glial cells are known
to produce neurons
– This is the first clear demonstration of this
phenomenon in mouse brains
C3 Blockade of Rho
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McKerracher, et al. reported
– C3 (a bacterial toxin which binds Rho) stimulates
functional improvement in rats with dorsal overhemisections, showing significant BBB score
improvements
– Now they report the first evidence of regeneration
in the C3 treated animals.
– They also report use of novel recombinant C3
molecules that penetrate the blood brain barrier in
animals, suggesting that these new drugs can be
used orally or systemically.
L2 CPG Stimulation
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CPG Stimulation in humans
– Background. Many studies have shown that the central
pattern generator exists in animals. Their presence in
humans was theorized but never shown.
– Milan Dimitrijevic showed data from 15 patients indicating
that high-voltage (10-15V), 30 Hz stimulation of L2 causes
activity changes that indicate locomotor function. Patients
that receive this stimulation can walk further.
– Richard Hermann at Good Sam at Arizona showed that such
stimulation significantly reduces the metablic energy and
fatigue required for walking in people with spinal cord injury,
suggesting that the CPG stimulation results in more efficient
activation of anti-gravity muscles.
AIT-082 Mechanisms
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AIT-082 is being tested in clinical trials of Alzheimer’s
disease and spinal cord injury. Several studies
provide clues of mechanisms:
– Brain neurotrophin levels increased by 100-200% in rats that
had AIT-082 in their drinking water.
– Stem cell proliferation assessed by BRDU labeling suggest
that a 20% increase in active stem cells in the brain and
spinal cord
– AIT-082 prevents sensory loss in diabetic rats
– AIT-082 does not bind purinergic receptors.
– Non-purinergic drugs are neuroprotective and neurotrophic
by promoting protein phosphorylation and not by increasing
ATP levels in brain
Enteric Glia
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Enteric glial cells
– Are present in myenteric plexi located in intestinal
muscle and submucosa layers
– are distinct from Schwann cells and can ensheath
groups of axons
– migrate in CNS and do not stimulate inflammatory
reaction in astrocytes
– promote dorsal root ingrowth into spinal cord when
transplanted to cord after dorsal root lesions
– represent an accessible population of glial cells
that can be transplanted to the spinal cord
Noxious Stimuli and BBB
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Jim Grau’s laboratory at Texas A & M
– Showed that training rats with 20-minute per day
conditional noxious electrical stimulation of the tail
can produce long-lasting behavioral effects,
lowered thresholds for withdrawal of foot
– Even a few hours of training can produce longlasting deleterious effects on locomotor
performance by BBB scores after contusion
injuries of the spinal cord
Nogo Receptor Blockade
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Stephen Strittmatter laboratory at Yale:
– Used fragments of the 66-amino acid active
domain of Nogo to bind and block the Nogo
receptor
– They showed that blockade of the Nogo receptor
allowed significant regeneration of corticospinal
tract through a spinal cord crush lesion
– Functional data is still not yet available
– Pictures of the regenerating axons indicate that
they are scattered over both ventral and dorsal
areas of the spinal cord below the injury site.
Minocycline
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Minocyline is neuroprotective
– Kiaei, et al from Cornell University showed that minocycline protects PC12
cells against NGF withdrawal and ischemia while Lin, et al. showed that
minocyline attenuates bilirubin neurotoxicity
– Festoff, et al. from Kansas showed that minocycline at 10 minutes, 6 hours,
and 24 hours after spinal cord contusion, remarkably improved locomotor
BBB scores by 3-4 points.
– Ulrich, et al. from Alberta showed that minocyline inhibits pro-inflammatory
cytokines in thiamine-deficient brains while Gulam, et al. showed that
minocyline reduces microglial activation.
– Zhang, et al. from Wisconsin showed that minocycline promoted survival of
transplanted neural progenitor cells
– He, et al. from Baylor showed that minocycline protected striatal cells
against 6-OH-DOPA. Likewise Wu, et al. from Columbia showed that
minocycline protects against MPTP but Yang, et al. from Cornell showed
that minocyline aggravates MPTP damage.
– Denovan-Wright from Dalhousie reports beneficial effects of minocycline in
two patients with Huntington’s chorea.
Summary
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These are only a few of many exciting studies that
were presented at the Society for Neuroscience
Treatments. Several new therapies are promising,
i.e. minocycline, C3 blockade of Rho, Nogo receptor
blockers, and AIT-082.
Stem cells. Stem cells are glia and that they are
more flexible that we had previously thought and we
have more sources of cells for transplantation than
before.
CPG stimulation improves walking in people with
spinal cord injury. Noxious stimulus-condition can
severely impair locomotor function in animals.