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Retinal Ganglion Cell Life and Death – Mechanisms and Implications for Ophthalmology
antioxidant proteins in animal models have shown promising also significantly increased RGC survival.
62
Indeed, a number of these
effectiveness in decreasing RGC death,
44
and a number of have demonstrated efficacy in animal models of RGC degeneration
antioxidants are entering clinical trials as neuroprotectants. and have been examined in clinical trials for other degenerative
diseases of the nervous system. There is a strong justification to
Any initial RGC death, particularly from ischaemia-induced necrotic transition such molecules to human trials for RGC neuroprotection.
release of cellular contents, can lead to secondary cell death, which
may be caused by excitotoxicity. Excitotoxicity is thought to occur Not only do RGCs depend on peptide trophic factors from their
when excessive activation of glutamate or other channels (e.g. from targets and other neighbours to survive, but they may also depend
glutamate spilling into the extracellular space from dying cells), and on physiological levels of electrical activity to survive. During
specifically of N-methyl-D-aspartate (NMDA)-sensitive glutamate development, RGCs wire into the retinal network and are depolarised
channels, leads to a deleterious increase in intracellular calcium and through gap junctions and chemical synapses. Considerable
subsequent activation of pro-apoptotic signalling pathways.
45
evidence points to a role for electrical activity in maintaining RGC
However, excitotoxicity is more complex than initially thought, and survival in the adult as well. RGC death is increased if electrical
depends on the duration, location and intensity of glutamate channel activity is blocked with tetrodotoxin.
63
Conversely, RGC survival is
activation,
46
as some level of electrical activity may be protective (see enhanced with physiological levels of electrical activity
22
in vitro and
below). In hippocampal neurons, neuroprotection has been shown to in vivo.
64
In a rat model of optic nerve injury, a single two-hour
be related to preferential activation of synaptic NMDA receptors, and session of transcorneal electrical stimulation (TES) of the retina with
excitotoxicity with activation of non-synaptic ones,
47
but this a bipolar contact lens electrode promotes RGC survival one week
interesting point has not been well explored in RGCs. This complexity after injury.
65
TES can stimulate RGCs in human patients
66,67
and is
may underlie the difficulty in using NMDA receptor blockade as a dependent on the pattern of electrical stimulation used,
68
raising the
therapeutic modality. A multicentre clinical trial using the low-affinity possibility of human clinical trials.
non-competitive NMDA antagonist memantine in patients with
primary open-angle glaucoma did not detect a signficant decrease in How does electrical activity enhance RGC survival? A number of
disease progression compared with placebo.
48
mechanisms may be at play. Activity can upregulate the production
of growth factors,
3,57,69
mainly by activating gene expression.
70
It is not clear whether the main contributor to excitotoxic RGC death is Depolarisation can elevate RGC levels of cAMP,
1,71
and both
necrosis or apoptosis. Studies in rats have found increased membrane depolarisation and cAMP elevation have the ability to recruit TrkB
permeability and cell body swelling consistent with necrosis;
49
receptors to the RGC membrane
72
and to enhance RGC
however, it is known that calcium can trigger apoptosis mediated by responsiveness to peptide trophic factors in vitro and in vivo.
72,73
the calcium-activated proteins calcineurin
50,51
and calpain,
9,52,53
both of These data raise the hypothesis that one of the reasons RGCs die
which are able to mediate apoptotic death of RGCs.
53
after injury is that they are less electrically active.
74
These external insults can also lead to other cellular dysregulation. How does electrical activity increase cAMP in RGCs? Increases in
For example, accumulation of abnormal proteins, such as cAMP and subsequent enhancement of neurotrophic responsiveness
hyperphosphorylated Tau AT8, have been described in the retina of likely depend on calcium-sensitive adenylyl cyclases (ACs).
75
Most
glaucoma patients.
54
Abnormal folding of proteins inside the attention has focused on the transmembrane ACs, which are
endoplasmic reticulum (ER) leads to ‘ER stress’ and severe cellular activated pharmacologically by forskolin, a drug that can potentiate
dysfunction, again associated with RGC apoptosis. ER stress is RGC trophic responsiveness in a manner similar to depolarisation.
22,56
present preferentially in the ganglion cell layer 24 hours after
intravitreal NMDA injection or elevation of the IOP.
55
The significance Recently, however, an alternative intracellular, soluble source of
of ER stress is still under investigation to determine whether the cAMP was described in somatic mammalian cells, called soluble AC
phenomenon is a cause or just part of the process of cell death. (sAC).
76
sAC is activated by several factors, including calcium,
bicarbonate, CO
2
and, probably, ATP.
77–80
sAC is ideally positioned to
Neurotrophic Deprivation, Decreased Electrical play a role in survival, being localised around and inside
Activity and Retinal Ganglion Cell Death mitochondria,
81–83
and its calcium responsiveness makes it a good
RGCs depend on trophic signals from their neighbours in the retina, in candidate to mediate activity-dependent survival. Inhibition of sAC
the optic nerve and in their targets in the brain for survival.
56
Target- activity in RGCs using 2-hydroxyestradiol
80
decreases RGC survival,
derived growth factors
3
such as brain-derived growth factor (BDNF) while the sAC agonist bicarbonate
84
increases survival and axon
are taken up by RGC axon terminals and travel retrogradely through growth in RGCs.
85
These data suggest that sAC may be mediating
the axon, down the optic nerve and back to the cell body in the some of the pro-survival responses to electrical activity that were
retina.
57
RGC dependence on target-derived BDNF seems to be more previously attributed exclusively to transmembrane adenylyl cyclase-
important during formation of early axon connections with their produced cAMP.
targets in the brain,
58,59
but may switch to dependence on other
sources, such as other retinal cells, including amacrine cells and Other signalling pathways are also modulated in activity-dependent
Muller glia during development and into adulthood.
60,61
Similarly, other neuroprotection, including the NFκB signalling pathway,
86,87
which
trophic factors, such as fibroblast growth factor-2 (FGF2), glial-derived mediates the effect of activity-dependent neurotrophic factor (ADNF)
neurotrophic factor (GDNF), insulin-like growth factors (IGFs) and and activity-dependent neuroprotective protein (ADPN). These
ciliary neurotrophic factor (CNTF), strongly support RGC survival. For peptides can rescue neurons from death after tetrodotoxin-induced
example, lentiviral-mediated transfer of CNTF into schwann cells activity blockage,
88
and peptides derived from ADNF (ADNF-9) and
placed in a peripheral nerve graft to repair rat optic nerve after injury ADNP (NAP) increase survival and axonal growth in RGCs cultured in
EUROPEAN OPHTHALMIC REVIEW 111
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