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Neuroprotection in glaucoma: present and future
CHEN Shi-da1, WANG Lu1, and ZHANG Xiu-lan1*
1
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun
Yat-Sen University, Guangzhou, 510060, P.R. China;
*
Corresponding to: Xiulan Zhang, State Key Laboratory of Ophthalmology,
Zhongshan Ophthalmic Center, Sun Yat-Sen University, 54S. Xian lie Road,
Guangzhou 510060, P.R.China; [email protected]. Tel:8620--87330484;
Fax:8620-87333271.
Acknowledgments: This research was supported by the grants from the National
Natural Science Foundation of China (81170849) and the Fundamental Research
Funds of State Key Laboratory of Ophthalmology (2011C02).
Keywords: glaucoma; neuroprotection; retinal ganglion cells
Abstract
Objective: To review the updated research on neuroprotection in glaucoma, and
summarize the potential agents investigated so far.
Data sources: The data in this review were collected from PubMed and Google
Scholar databases published in English up to September 2012, with key words
including glaucoma, neuroprotection, and retinal ganglion cell (RGC), both alone and
in combination. Publications from the past ten years were selected, but important
older articles were not excluded.
Study selection: Articles about neuroprotection in glaucoma were selected and
reviewed, and reference lists of articles identified by this search strategy and judged
relevant to this review were also included.
Results: Although lowering the intraocular pressure is the only therapy approved as
being effective in the treatment of glaucoma, increasing numbers of studies have
discovered various mechanisms of RGC death in the glaucoma and relevant
neuroprotective strategies. These strategies target neurotrophic factor deprivation,
excitotoxic damage, oxidative stress, mitochondrial dysfunction, inflammation,
activation of intrinsic and extrinsic apoptotic signals, ischemia and protein misfolding.
Exploring the mechanism of axonal transport failure, synaptic dysfunction, the glial
system in glaucoma, and stem cell used in glaucoma constitute promising research
areas of the future.
Conclusions: Neuroprotective strategies continue to be refined, and future deep
investment in researching the pathogenesis of glaucoma may provide novel and
practical neuroprotection tactics. Establishing a system to assess the effects of
neuroprotection treatments may further facilitate this research.
INTRODUCTION
Glaucoma is the second leading cause of blindness worldwide1. It is recognized to be
an optic neuropathy accompanied by typical structural and functional defects (optic
disc damage and visual field loss) in at least one eye2. It is widely accepted that the
death of a substantial number of retinal ganglion cell (RGCs) in the inner retina and
the loss of their axons in the optic nerve are the pathophysiologic characteristics of
glaucoma2. Several well-known clinical studies have demonstrated that intraocular
pressure (IOP) lowering is currently the only effective treatment of primary
open-angle glaucoma (POAG) and of ocular hypertension; the treatment not only
delays or prevents the onset of POAG in individuals with elevated IOP, but also partly
prevents visual loss in cases of POAG. Nonetheless, the reduction of IOP is not
always successful and many patients continue to experience progressive visual loss, as
indicated in the OHTS (Ocular Hypertension Treatment Study), CIGTS (Collaborative
Initial Glaucoma Treatment Study), and EMGT (Early Manifest Glaucoma Trial)3,4,5,6.
Moreover, achieving adequate pressure lowering may be difficult or may be
associated with adverse effects7. Neuroprotection offers potential as a complementary
therapy to IOP lowering, and also serves as an alternative therapy for when
IOP-lowering agents are not used, not tolerated, or not effective8. Generally, IOP
lowering could obstruct or delay the progress of visual loss in the glaucoma, and it is
indirectly neuroprotective. However, by definition, glaucoma neuroprotection is
considered to be independent of IOP lowering, as it directly targets neurons within the
central visual pathway, especially the RGCs8,9. Neuroprotective agents focus on the
multiple pathogenic mechanisms that result in axonal degeneration and RGC death.
Mechanisms of RGC death in glaucoma and neuroprotection strategies
The molecular basis of RGC death in the glaucoma stemming from animal models
include neurotrophic factor deprivation, excitotoxic damage, oxidative stress,
mitochondrial dysfunction, inflammation, activation of intrinsic and extrinsic
apoptotic signals, ischemia, protein misfolding, axonal transport failure, synaptic
dysfunction, and misbehaved glial system in retina. There has been considerable
progress in our understanding of the multiple pathways that lead to RGC death in
glaucoma.
1. Neurotrophins
Neurotrophins play a key role in the development, differentiation, and survival of
RGCs; they include nerve growth factor (NGF), brain-derived neurotrophic factor
(BDNF), and neurotrophin3/4/5 (NT-3/4/5). The biological effects of these
neurotrophins are mediated by two classes of cell surface receptors: 1) the
tropomyosin-related kinase (Trk) family, consisting of TrkA, the receptor for NGF,
TrkB, the receptor for BDNF and NT-4/5, and TrkC, the receptor for NT-3; and 2) the
p75 receptor (p75NTR), which binds all neurotrophins with a similar affinity10.
Activation of Trk receptors has been typically associated with cell survival, while
p75NTR can stimulate both survival and apoptotic pathways11,12. Anything that induced
the neurotrophins deprivation—including interrupted transportation from the upper
neurons, low expression level of receptor, and gene mutation—will cause RGC death,
and thus delivering neurotrophins to the RGCs will have a protective effect. NTF4
gene mutations have been found in 1.7% of POAG patients of European origin; the
mutations showed a decreased affinity of NT-4 with TrkB, thus leading to disease
progression13. One study finds that after receiving murine neurotrophic growth factor
eyedrops once daily for three months, three advanced glaucoma patients showed
improvement in all parameters of visual function14.
Among the neurotrophins, BDNF has received particular attention because of its
potential role in the survival of RGCs. BDNF promotes neuronal survival by
inhibiting default apoptotic pathways. The direct application of recombinant the
BDNF or viral vector-mediated BDNF expression has been found to protect RGCs in
the optic nerve section model or high IOP glaucoma model15,16. Glial cell line-derived
neurotrophic factor (GDNF), another neurotrophin, is less effective than BDNF in
protecting injured RGCs, but when GDNF is combined with BDNF, the effect is
almost doubled compared to the independent administration of each neurotrophic
factor17. BDNF is also an important regulator of synaptic plasticity18, and of
position-dependent branching of developing RGC axons19. In the retina, BDNF
contributes to the shaping and maintenance of RGC dendritic morphology following
axonal injury20. Ciliary neurotrophic factor (CNTF) is a cytoplasmic protein that acts
as an endogenous response to retinal neurons under pathological conditions. In the
adult rat retina, CNTF is primarily localized in Müller cells, and its expression
increased after axotomy and ischemia, and in experimental glaucoma21,22.
Overexpression of CNTF promotes RGC survival in laser-induced glaucoma models23.
Exogenous CNTF exhibits moderate protection for RGCs in different models23,24;
however, unlike BDNF, CNTF is able to stimulate RGC axon regeneration after
injury25. One disappointing fact is that excess exogenous CNTF could impair visual
function; thus the concentration of CNTF used in the retina must be monitored26.
However, there are obstacles to using the neurotrophins in the eyes, including 1) the
short half-time of these neurotrophins; 2) the low permeability of the blood-brain
barrier; 3) the demand for high doses; 4) the insufficient to stimulate the regrowth of
injured RGC axons; and 5) the low level of the neurotrophin receptor in injured RGCs.
As a result, most of the research currently focuses on 1) developing a novel drug
delivery, in the hope of increasing the drug concentration for the eye and raising the
function time; 2) finding a new neurotrophic analogue, such as the small peptide,
which has a high facility to cross the blood-brain barrier and a longer
half-time27,28(the small peptides ADNF-9 and NAP not only increased the survival but
also supported neurite outgrowth of rat RGCs in vitro29); 3) facilitating the selective
upregulation of TrkB in RGCs combined with exogenous or endogenous BDNF to
enhance the duration of level of BDNF-induced neuroprotection30; and 4) combining
the application of factors with independent mechanisms, which has shown that the
combination of basic fibroblast growth factor, neurotrophin-3, and BDGF delivered to
the RGC not only prevents RGC loss but also promotes axon growth after CNS injury.
This effect exceeds that of the each neurotrophic factor alone31.
2. Excitotoxicity
It is universally accepted that abnormal high extracellular levels of glutamate could
activate the NMDA receptor (NMDAR ) channels in RGCs, leading to the deleterious
increase of intracellular calcium and nitric oxide production, and the activation of
pro-apoptotic signaling cascades, which result in the death of RGCs32. A great number
of studies have demonstrated that exogenous NMDA induced the rapid death of adult
RGCs, and excess glutamate has been found in the retina in glaucoma33, while
inhibitors of NMDAR or downstream pathways have a protective role in experimental
models of retinal ischemia and glaucoma34, 35. However, several studies demonstrated
that there was no excessive glutamate found in experimental animals with ocular
hypertension or in human glaucoma36,37. Thus, there may be no drastic elevation or
accumulation of glutamate in chronic and progressive glaucoma, and a glutamate
increase is likely to occur in the localized area of the retina at any one time. On the
other hand, extracellular Mg2+ regulates the NMDAR under different membrane
potential, which may lead to NMDAR activation even at physiological levels of
glutamate38, 39. This contradiction reminds us of how complex a mechanism glutamate
is to the RGCs, and how it is not enough to simply rule out an excitotoxic component
in RGCs to achieve a protective effect. The glutamate will not only be released by
astrocyte or microglial cells exposed to ischemia or high IOP, but the initial
degeneration of some RGCs seems to lead to a toxic environment such as glutamate
excitotoxicity32. This may be the reason that injured RGCs result in secondary
damage to the surrounding, normal RGCs, which in turn leading to progress of
glaucoma. Modulation of the NMDA receptor has always been a major area of
research in glaucoma neuroprotection. There are several anti-excitotoxic drugs that
have been investigated to have a neuroprotective effect.
Memantine, an uncompetitive antagonist of the NMDA receptor that was approved by
the FDA for treating Alzheimer’s disease, blocks only excessive NMDA receptor
activity while displaying weak potency during normal synaptic transmission by
glutamate9,33. It had been found to protect against optic nerve fiber loss, neuronal
shrinkage within the central visual pathway, and loss of visual function in monkey
hypertension glaucoma models40, 41. Nevertheless, the result of a phase Ⅲ clinical
trial in the human open-angle glaucoma was disappointing, which may be due to the
inappropriate
endpoint
and
insufficient
duration
of
the
study42.Another
non-competitive antagonist of the NMDA receptor is MK801, which shows a strong
protective effect on the RGCs both in vitro and in vivo43, 44. However, because of its
high affinity with the NMDA receptors and long dwell time in the channel, which
results in a large neurotoxic effect, it cannot be used clinically. Finding a drug with
the same protective effect as MK801 but with less neurotoxic effect or combining
MK801 with other agents to reduce the adverse effect would be helpful.
3. Oxidative stress
Oxidative stress, characterized by the imbalance between the production of reactive
oxygen species (ROS) and their elimination system, plays an essential role in the
injury and death of neuron cells, including RGCs. Excessive ROS could cause protein
modification and DNA damage, consequently activating cell death signals45. ROS can
be caused by mitochondrial dysfunction, abnormal protein folding, and a defective
ubiquitination and proteasome degradation system46. It has been confirmed that
oxidative damage occurs in experimental models of optic nerve injury and in human
glaucoma, and insufficiency in ROS-neutralizing mechanisms in RGCs were also
discovered in glaucoma47-49. As a result, keeping the ROS production system and
clear-up system balance would benefit the RGCs’ survival50, 51. The regulation of
cellular redox status is provided by the glutathione and the thioredoxin (TRX) systems.
Overexpression of TRX1 and TRX2 protected RGCs from pharmacologically-induced
oxidative stress, ocular hypertension52.
Melatonin, a potent, naturally occurring antioxidant with free-radical scavenging
activity, displays a critical role in aqueous humor circulation and shows potential as a
neuroprotectant. Melatonin was shown to prevent RGC loss in the NO-induced retinal
damage model53. Ginkgo Biloba, which is part of traditional Chinese medicine, has
been used to treat Alzheimer’s disease and low-tension glaucoma54, 55. Its extract
EGb761 showed robust antioxidant qualities, inhibiting chemically induced apoptosis.
Moreover, EGb761 decreased high IOP-induced RGC loss56, 57.
4. Mitochondrial dysfunction
The mitochondrial is an organelle in which the interaction between anti- and
pro-apoptotic Bcl-2 family members occurs. When the trend is toward apoptosis,
mitochondrial membrane permeability increases and releases cytochrome c,
subsequently forming an apoptosome with Apaf-1 and procaspase-9 and leading to
cell death. The early release of cytochrome c in injured RGCs was showed in optic
nerve axotomy58. However, the specific role of mitochondrial mediators in RGC death
in glaucoma remains poorly explored.
RGCs have a high metabolic activity and energy demand, which is confirmed by the
large amount of mitochondrial in RGC soma and the intraretinal portion of their
axons59. Mitochondrial DNA damage increases with age and with the reduced
production of ATP in the RGC, compromising RGC viability. As a result,
mitochondrial dysfunction could play a key role in glaucoma. It is found that
decreased ATP availability leads to cellular energy crisis, interrupting the normal
transduction of action potential along RGC axons60. ATP content in the mouse optic
nerve dropped with age and high IOP in DBA/2J mice, leading to RGC axon
dysfunction61. However, excess ATP release from injured and dying cells to the
extracellular place, thus activating the 2X7 receptor, would be toxic to the RGCs62.
Mitochondrial biogenesis-based neuroprotection is intended to restore the balance of
ATP levels, increasing their available energy supply63,
64.
PGC-1α is a key
mitochondrial biogenesis factor. The regulation of PGC-1α has been explored in many
mitochondrial-related
diseases, such
as
cancer,
neurodegenerative
diseases,
cardiovascular disease65, it remains poorly explored in glaucoma64.
Coenzyme Q10, a component of the mitochondrial electron transport chain that
promotes ATP production, is multifactorial in its neuroprotection of RGCs. It has been
confirmed that Coenzyme Q10 not only mediates the electron transport chain but also
displays antioxidant properties, which show a strong protective effect for RGCs both
in vivo and in vitro66, 67.
5. Inflammation and immunological strategies
In the CNS, boosting a self-specific immune response promotes recovery. Growing
evidence in clinical and experimental studies strongly suggest the involvement of the
immune system in glaucoma68. Present research findings collectively suggest that
innate immune cells, autoreactive T cells, autoantibodies, and complement activation
may impair RGCs and increase the susceptibility to disease progression in glaucoma68,
69.
And the role of glial cell in the inflammation and immune response in the
glaucoma would discuss in another section bellow.
TNF-α is a pro-inflammatory cytokine that acts on two distinct receptors, TNFR1 and
TNFR2. It serves as a critical element in immune homeostasis and in mediating
apoptosis. In the retina, TNF-α is mainly produced by Müller glia70, and TNF-α
upregulated in experimental and human glaucoma71, 72. Moreover, the level of the
TNF-α increased in the aqueous humor of glaucoma, and TNF-α gene polymorphisms
have been correlated with POAG73, 74. Intravitreal TNF-α injection has a similar effect
to the ocular hypertension glaucoma mouse model; blocking the TNF-α signaling
could guard against the loss of RGCs71. TNF-α mediated RGC death in a
caspase-independent event, but may mediate the insertion of Ca2+ -permeable
AMPAR during excitotoxic injury and increase RGCs susceptibility to damage70, 75.
Anti-inflammatory drugs’ targeting of the TNF-α signaling pathway has been fully
explored, and the most promising one is Copolymer-1(Cop-1), which has been
approved to treat multiple sclerosis (MS)76. Cop-1 binds to the relevant major
histocompatibility complex proteins and leads to the activation of T suppressor cells,
triggering a neuroprotective autoimmune response77. It has been demonstrated to
protect the RGCs in vivo in the rat model of optic nerve crush77, in the high-IOP
model78, and against glutamate-induced excitotoxicity79.
6. Anti-apoptotic strategies and gene therapy
The apoptosis of the RGCs have been demonstrated in different kinds of animal
models inducing RGCs loss. The apoptotic process can be triggered by various stimuli
and involves intrinsic and extrinsic pathways, which are the subject of intense
research in the quest for molecular targets to prevent RGC death in glaucoma.
Apoptosis signal regulating kinase1 (ASK1) which is primarily expressed by RGC,
has an important role in stress-induced RGC apoptosis80. Increased RGC survival and
decreased degenerating axons in the optic nerve were observed in the ASK1 null
mice81. The downstream factor of the ASK1 are called JNKs and have ten different
isoforms, which display differential specificity toward their target82, playing a key
role in the survival of the RGCs. Deleting one kind of JNK gene, the JNK3, did not
prevent RGC loss in the ocular hypertension models; nonetheless, both eliminating
the JNK2 and JNK3 showed a significant RGC-protective effect after injury83, 84. This
may suggest that different JNK isoforms serve to compensate for deficiencies in this
pathway to ensure RGC apoptosis. Generally, the anti-apoptotic Bcl-2 and
pro-apoptotic Bax genes play an important role in the survival of the RGCs.
Overexpression of either the Bcl-2 or Bcl-XL gene prevents RGC loss in optic nerve
crush models85,
86.
On the other hand, deleting the bax genes result in RGC
neuroprotection when subjected to optic nerve crush models or in a genetic model of
glaucoma87, 88.
The common pathway that the intrinsic and the extrinsic apoptotic have is activating
the caspase family, including caspase-9/3, caspase-8, so the inhibition of caspases to
protect RGC is a promising strategy. Whether one uses an intraocular injection of
caspase inhibitors or gene therapy to lower the expression of the caspases, they all
show modest RGC protection32,
89.
A combination of overexpression for both
BIRC4/XIAP (a protein directly inhibiting caspase-3,7,9) and GDNF had a synergistic
effect on the survival of axotomized RGCs90. Therefore, the strategy to target multiple
anti-apoptotic pathways appears to be a promising method to prevent RGC loss in
glaucoma.
7. Protein Misfolding
More and more evidence has demonstrated that glaucoma is a progressive
neurodegenerative disease32, 91, similar to Alzheimer’s in that both have aggregates of
amyloid-β92. Glaucomatous retinopathy and visual field loss are more likely for
people with AD91. Research has found that Aβ localizes with apoptotic RGCs in
experimental glaucoma and induced RGC apoptosis93. Thus, obstructing the Aβ
pathway
provides
a
therapeutic
avenue
in
glaucoma
management.
N-benzyloxycarbonyl-Val-Leu-leucinal (Z-VLL-CHO), a kind of β-secretase inhibitor,
has been found to reduce RGC apoptosis both in vitro and in vivo94. Using the agents
that target Aβ, including β-secretase inhibitors, Congo red, and anti-Aβ antibodies, is
more effective than monotherapy93.Hot shock proteins (HSPs) is a group of molecular
chaperones that helps to form and maintain the proper conformation of other proteins
and prevent abnormal protein aggregating in the cell body95. Increased
immunostaining of HSP 60 and HSP 27 has been confirmed in the glaucomatous
eyes96; using geranylgeranylacetone (GGA) to promote the HSP 27 expression in the
RGCs has reduced RGC loss in high-IOP animal models97. However, it is still poorly
known how these HSPs function in the glaucoma.
8. Ischemia and drugs
Research has shown that dysfunction of the microcirculation at the optic nerve head
plays an important role in glaucoma, which may be caused inherently or by high
IOP98. High levels of the endothein-1(ET-1) have been found in the aqueous humor of
glaucoma patients99, and intravitreal injection of ET-1 could impair axonal transport
in RGCs, which may constrict the microvasculature of the optic nerve head and
retina100,
101.
Calcium-channel
blockers
(CCBs)
have
antivasospastic
and
anti-ischemic effects. Lomerizine alleviates secondary degeneration of RGCs in an
optic nerve crush model102, 103, while a study of the effect of nilvadipine, a calcium
antagonist, showed that it slightly slowed the visual field progression, maintained the
optic disc rim, and increased posterior choroidal circulation after three years of
following up104. However, more attention should be paid to the potential of the CCBs’
reducing the optic nerve head perfusion pressure105.
9. Others
Brimonidine, a drug previously shown to be neuroprotective in the laboratory, may
have had a beneficial effect on visual function independent of IOP lowering in a
low-pressure glaucoma treatment study106. L-N(6)-(1-iminoethyl)lysine 5-tetrazole
amide, a prodrug of an inhibitor of inducible nitric oxide synthase, decreased
generation of the nitric oxide at the optic nerve head could mitigate the RGC loss in a
rat model of glaucoma107.
Promising research areas in the future
1. Axonal transport failure and synaptic dysfunction
For RGCs to survive, they and their target neuron cells in the lateral geniculate
nucleus (LGN) must be successfully linked to exchange information and acquire
sufficient neurotrophic factors. However, deficits in both anterograde and retrograde
axonal transport in the optic nerve have been observed in animal glaucoma models
and in human high-pressure secondary glaucoma108, 109. When subject to high IOP,
retrograde transport of BDNF was impaired and dynein (a motor protein required for
axonal transport) accumulated at the optic nerve head and retinal110, 111. More and
more evidence suggests that the primary injury in the glaucoma is the deficit in
retrograde axonal transport, which occurs early and progresses in a distal-to-proximal
pattern112. More interestingly, the RGC axons and their presynaptic neurons persist in
the colliculus well after transport fails. This means that restoration of transport along
RGC axons might be an early therapeutic target for glaucoma112. Furthermore,
detecting the damage of the axonal transport in the glaucoma will provide us with the
clues for early diagnosis and the time for early intervention.
The synaptic connectivity dysfunction may also be an early characteristic in glaucoma.
Many studies have demonstrated that RGC dendritic thinning, reduced arbor
complexity, and arbor retraction occurred prior to RGC shrinkage and axon atrophy113,
114.
Reduced levels of c-fos, a marker of neuronal connectivity, happened early in
ocular hypertension rats115, and morphological changes to the RGC dendrites related
to a reduction in the spatial and temporal response to visual stimuli may underlie
functional deficits in glaucoma116. Finding a way to detect the early damage of
dendrites will provide us with an early clue to the diagnosis, and discovering methods
to preserve the normal function of synaptic connectivity will offer promising
strategies to treating glaucoma.
2. Glial cell system
An interesting issue has occurred in the field of glaucoma neuroprotection: The
traditional RGC-centric view of neurodegeneration in glaucoma has changed,
acknowledging that other retinal- and optic-nerve cells actively contribute to RGC
death. The neuron-glia interaction in the retinal and optic nerve head has received
considerable attention. Astrocytes, Müller cells, and microglial cells in the retinal
nerve were proposed to play both protective and deleterious roles in glaucoma. They
are also the key resident immune cells in the retina and optic nerve, thus playing a key
role in immune response in glaucoma.
Astrocytes play a key role in the remodeling of the optic nerve head during
glaucomatous damage117, which is confirmed by the fact that astrocytes proliferated at
the optic nerve head and astrocytosis has been observed in the LGN and visual cortex
in human glaucoma and animal glaucoma models118, 119. Recent studies found that the
astrocytes at the myelination transition zone, which express phagocytic marker Mac-2,
enhanced the capability of phagocytose RGC axonal processes, suggesting that this
degradative
pathway
for
axons
might
contribute
to
glaucomatous
neurodegeneration120. In addition to modulating the optic nerve head environment,
astrocytes are also known to produce neurotoxic molecules when subject to injury,
which in turn leads to RGC death121, 122.
Müller cells, the most abundant retinal glia cell type, are among the first responders
following IOP increase. Reactive Müller cells in glaucoma could increase the
susceptibility of RGCs to stress signals and contribute to disease progression123.
Deficit in the potassium buffering system, water clearance, or production of
antioxidant molecules by Müller cells could impair RGC function in glaucoma70.
Moreover, Müller cells also take part in the oxidative stress in the RGC70. One
exciting discovery is that Müller cells are endowed with stem cell properties and are
being explored as a potential source of neural replacement and transplantation in the
injured visual system124, 125. Nonetheless, the exact role the Müller cells play in the
glaucoma and what people could do to modulate the Müller cell to have a protective
role are still vastly underexplored.
Microglia are specialized innate immune cells that reside in the retina and the brain.
Microglia could change from a quiescent state to an activated state when the
microenvironment changes, with their morphology and cell-surface molecules
transforming, leading to the clearance of toxic debris and release of neurotrophic and
anti-inflammatory factors126-128. However, over-activation of the microglia results in
detrimental effects on neurons129, 130. Reactive microglia has been observed in the
retina and optic nerves from axotomized eyes during ocular hypertension and human
glaucoma131. Inhibition of microglia over-activation with minocycline delayed RGC
death in the animal models132. However, more research is needed to explore in-depth
the potential therapeutic role microglia play in glaucoma.
3. Stem cells
Neuroprotection aims to halt or slow the death of RGCs and their axons in the
glaucoma, but how does one compensate for the loss of RGCs? Stem cell
transplantation may provide a promising new avenue for treating glaucoma. There are
two prospects for cell transplantation-based treatment modalities: neuroprotection and
RGC replacement. Interestingly, research shows that the transplantation of stem cells
secretes high levels of neurotrophins, including NTFs, which have a protective effect
on RGCs in experimental glaucoma133,
134.
There has been great progress in the
regeneration of RGCs, which provides encouragement that RGC replacement may be
possible135-137. However, obstacles remain, including how to acquire functional RGCs
from the stem cells, how to optimize for maximal engraftment and integration into the
host retina, and how to promote the excellent synaptic connection with the brain. All
of these questions require a great deal more research.
Challenges and assessment of the neuroprotection strategies
There is great diversity to the molecular signals in the glaucoma, and it is highly
plausible that different molecular pathways are activated at different stages of
glaucoma onset and progression32. Identifying the exact issues that occur at the
particular stages is essential if one is to combine the various therapies targeting
different mechanisms. Every RGC should also have its own receptor profiles and
unique individual characteristics, allowing each one to respond differently to injury.
This means that apoptosis can be triggered in different ganglion cells for different
reasons and at different times; as a result, an agent with only a single mode of action
may not completely protect all the RGCs. Understanding these issues better will help
us develop personalized therapies for neuroprotection in glaucoma.
What is more, it is still difficult to detect the progressive glaucomatous injury,
although techniques for imaging the living RGCs have developed in animals138, 139. At
present, the endpoint of the study depends on measuring the functional injury, such as
the visual field, but it does not take into account the structural alterations in the optic
nerve or retinal nerve fiber layer. Moreover, the duration of clinical trials of
neuroprotection may be longer as glaucomatous optic neuropathy is a slowly
progressive disease.
R.N. Weinreb suggested a criterion for evaluating a glaucoma neuroprotective agent’s
potential8: “First, the drug should have a specific receptor target in the retinal or optic
nerve. Second, the drug must reach the retinal or optic nerve in pharmacologically
effective concentrations. Third, evidence must be obtained in animal models that
activation of the target triggers pathways that enhance neuronal survival or decrease
neuronal damage. Fourth, the neuroprotective activity must be demonstrated in
randomized, controlled, clinical trials in humans”. Based on the above criterion, we
should consider the following issues before we find an effective neuroprotective agent,
the exact pathogenesis of the glaucoma, the optimal glaucoma animal models, and an
appropriate clinical assessment system.
CONCLUSIONS
Although there is strong or convincing laboratory evidence that several drugs provide
neuroprotection in glaucoma, only a minority of these investigations has led to
approved therapies, and the road to the implementation of neuroprotection in
glaucoma is still long. The evidence from randomized clinical trials is still lacking. A
considerable investment in genetic studies and molecular investigations may yield
more progress.
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Figure1
Multiple pathogenic mechanisms that result in axonal degeneration and RGC death in
glaucoma