Introduction:
Optic neuropathies are a group of conditions that result in the compromised function of the optic nerve. The retinal ganglion cells (RGCs) are a particular type of retinal neuron that form the optic nerve. These cells get damaged in certain areas. Though the clinical manifestations and causes of optic neuropathies vary, but all of them are a cause of blindness, which is irreversible due to self-renewal incapability and the limited self-repair ability of RGCs. To manage and prevent blindness, several approaches are being studied to avoid additional RGC degeneration and to substitute the degenerated cells.
Glaucoma is the most common among optic neuropathies, contributing to more than 18 million cases of blindness globally. It occurs as a cumulative retinal ganglion cell (RGC) neurodegeneration accompanied by a particular degeneration of the axons and their death in the optic nerve.
What Is the Role of Neuroprotection in Glaucoma and Its Significance?
Elevated IOP (intraocular pressure) is a predominant factor of all the causative factors leading to injuries of RGCs and axons. Irrespective of the etiology, in glaucoma, RGCs die by apoptosis (programmed cell death).
Apoptosis or RGC pathologies occur by reactive oxygen species, chronic intermittent ischemia, defective axon transport, etc. Increased IOP elevation directs to lamina cribrosa (on the inner surface of the optic nerve head, it configures optic cup bottom) distortion, guiding to axoplasmic inactivity, which further acts as a hindrance for the brain neurotrophic factors (help in neuron survival) from reaching the RGCs.
Besides raised IOP, various other factors such as age, race, and genetic history may play a notable role in the occurrence of glaucoma. For example, IOP is low in normal-tension glaucoma, but a typical glaucomatous optic neuropathy is observed, contributing to a major proportion of open-angle glaucoma cases.
Neuroprotection is a type of treatment in which neuronal death or deterioration is prevented to treat particularly central nervous system diseases like Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, etc. Neuroprotective therapies in glaucoma may prevent ischemia and oxidative damage, thus avoiding apoptosis of RGCs and optic nerve damage. Several classes of drugs are used in neuroprotective therapies.
Specific criteria have been set to assess the potency of a pharmacological drug as a neuroprotectant in glaucoma. These are listed:
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It must have particular target receptors in the retina or optic nerve.
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It must be supported by laboratory evidence that its mechanism of action improves neuronal resistance to injury.
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It must have availability at the retina or optic nerve in effective pharmacological concentrations needed for a neuroprotective action.
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It must have shown neuroprotective effects in prospective randomized clinical trials.
The various neuroprotective agents used are listed as follows:
Antiglaucoma Medications:
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Alpha-2 adrenergic agonists.
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Prostaglandin analogs.
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Beta-blockers.
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Carbonic anhydrase inhibitors.
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ROCK (Rho kinase) inhibitors.
Antioxidants:
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Gingko biloba extract.
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NMDA (N-methyl-D-aspartate) receptor antagonist.
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Citicoline.
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Crocus sativus.
Vasodilators:
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Calcium channel blockers (CCBs).
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Carbonic anhydrase inhibitors.
What Is Optic Nerve Neuro-regeneration and How Is It Done?
Improving the survival of RGCs is an essential primary step for already injured RGC axons in the optic nerve. Only apoptosis prevention is insufficient to upgrade the axonal regrowth back to brain targets. However, RGC protection from death may be enough in certain diseases where axon survival from a temporary causative agent is needed, like acute angle closure glaucoma and ischemic optic neuropathy. But, in the prolonged presence of an insult, when axons are severely damaged, treatment therapies should also include axon regeneration to restore the eye connections to the brain.
Cell Replacement in Neuro-regeneration:
Cell replacement-based therapies are required, particularly for end-stage optic neuropathies. With the emergence of human embryonic stem cells (hESCs) and inducible pluripotent stem cells (iPSCs), the idea of optic nerve regeneration has become a reality. Several well-grounded techniques have evolved to differentiate pluripotent cells into RGCs by using 2D planar and 3D organoid cultures.
The various neuro-regeneration adjuvants used are:
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Electrical field stimulation.
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Fabricated scaffolds.
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Autologous grafts.
Improving Intrinsic Growth Ability by Blocking Inhibitory Signals:
RGC axons stop growing due to the glia's release of inhibitory molecules. Scientific research has recognized many of these molecules, and subsequently, several drugs were produced as their antagonists. Other clinical targets could be the signaling pathways in the axons that act as mediators for such signals.
Other procedures to change the intrinsic ability of RGCs for axon regeneration include laboratory-based methods. Gene therapies may be used to target transcription factors like Kruppel-like factors. The growth-enhancing and regeneration-enhancing activities of mTOR (mammalian target of rapamycin) and CNTF (ciliary neurotrophic factor) can be activated by blocking some signaling factors like phosphatase and tensin homolog (PTEN) and suppressing cytokine signaling-3 (SOCS3).
Neurotrophic Factors:
BDNF (brain-derived neurotrophic factor), CNTF (ciliary neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), and NGF (nerve growth factor) have been proven to provide neuroprotection as well as neuroregeneration of RGCs in laboratory models of glaucoma. In clinical studies, their positive results devoiding of any associated complications or adverse effects are still awaited.
Surgical Approach:
Different surgical methods are being investigated to improve the regeneration of RGCs with the help of a simple lens injury. A single needle poke can induce an inflammatory response that enhances growth and survival by breaching the lens capsule. It may approve helpful in the regeneration of axons in most chronic glaucomas in the future.
Conclusion:
Glaucoma is a critical concern for eye health, so clinical studies are necessary to assess the role of neuroprotective and neuro-regenerative therapies in preventing its development and progression. Studies on non-IOP dependent neuroprotective therapies and neuroregeneration for glaucoma are growing, and some of these may prove helpful tomorrow for clinical use. Despite many advances and ongoing research, RGC protection is still a threat in glaucoma treatment and prevention.
