Neuroprotection in Glaucoma Management

Optic neuropathies, such as glaucoma, involve the degeneration of retinal ganglion cells (RGCs) and their axons, which culminate to make up the optic nerve. Because axons, RGCs, and the optic nerve belong to the central nervous system, their ability to repair themselves intrinsically is limited. Thus, various therapeutic attempts to replace damaged cells or prevent further degeneration using multiple potentially neuroprotective and neuro-regenerative techniques have been attempted.

In the case of glaucoma, an optic neuropathy characterized by progressive degeneration of RGCs sensitive to IOP-induced stress, neuroprotection refers to the prevention of RGC damage independent of reducing IOP.¹ Due to the neurodegenerative aspect of glaucoma progression, lack of therapies targeting RGC and axonal death is a major barrier of current glaucoma management, which is limited to lowering IOP.² As a result, research on neuroprotection of RGCs is of tremendous clinical importance.

COMPOUNDS UNDER INVESTIGATION FOR NEUROPROTECTIVE EFFECTS

Brimonidine Tartrate

Brimonidine tartrate, an alpha-2 adrenergic agonist, effectively reduces IOP when applied topically through a dual-action mechanism. Although its effectiveness at reducing IOP in the clinical management of patients with glaucoma is known, the potential role of brimonidine in neuroprotection has been demonstrated primarily in laboratory research, with only a few attempts in human clinical trials.³

In a study involving rats with ocular hypertension, a group treated with brimonidine tartrate was compared with a control arm that was given timolol. Each group showed a similar reduction in IOP after systemic administration, but the rats treated with brimonidine experienced 50% less RGC death compared with the control group. These findings suggest the improved survival rate of RGCs with brimonidine is likely due to its neuroprotective effects, independent of IOP reduction.⁴ A similar study was performed in a human clinical trial comparing visual field progression,⁵ and although there were some concerns in the interpretation of the results,⁶ the findings suggested less progression in the group treated with brimonidine compared with the control group.⁵ To reiterate, this result is controversial, so there is need for confirmatory studies to verify outcomes of treatment with brimonidine tartrate in humans.

Memantine

Memantine is an N-methyl-D-aspartate receptor antagonist used to treat Alzheimer disease and other neurologic conditions.¹ This type of receptor plays a role in the transmission of signals between nerve cells, and their overactivation can contribute to the neurodegenerative processes leading to neurologic disease. Due to the ability of memantine to modulate activity of these receptors and prevent excessive stimulation, research on this compound as a neuroprotective agent has been prevalent.

In a large, randomized clinical trial involving 2,298 patients, the potential neuroprotective properties of oral memantine in patients with primary open-angle glaucoma was examined over 48 months.⁷ However, assessment of visual field defect progression and glaucomatous optic nerve cupping in patients receiving 20 mg oral memantine daily compared with those receiving a placebo revealed no discernible difference in progression between the groups. Despite limited evidence supporting the role of memantine in neuroprotection, ongoing clinical analyses are actively exploring this further.⁷

Ripasudil

Another compound being studied for its role in neuroprotection is ripasudil, a Rho kinase (ROCK) inhibitor that is approved in Japan for the management of glaucoma by reducing IOP topically. In addition to elevating IOP, ROCK promotes inflammation, which can chronically damage RGCs. This effect provides the rationale for research on ROCK inhibitors as potential neuroprotective agents due to their antiinflammatory activity.

In a 2017 preclinical study, 19 rats were divided into groups receiving intravitreal tumor necrosis factor (TNF) alone, TNF and ripasudil, or ripasudil alone.⁸ Artificially elevated TNF promotes increased levels of inflammation that can lead to RGC and axonal death. Analysis of RGC and axonal loss within study groups after 3 weeks yielded a moderate decrease in axonal loss in the group receiving TNF and concurrent ripasudil compared with TNF alone. Furthermore, axons in rats receiving ripasudil alone demonstrated increased autophagy, indicating a more efficient removal of dysfunctional cellular components.

This study provides promising preclinical evidence of neuroprotection of ripasudil in both inflammatory and noninflammatory states; however, minimal clinical research has been conducted on the role ROCK inhibitors play in neuroprotection.

POTENTIAL REGENERATIVE THERAPIES

Insulin

The use of insulin in the treatment of various neurologic disorders is an area of immense interest in research. Aside from its well-known role in glucose metabolism, recent research has been geared towards the potential neuroprotective effects of this hormone. Insulin signalling is associated with synaptic plasticity, modulating the ability of synapses to strengthen or weaken over time.⁹ Moreover, insulin can act as a neurotrophic factor, promoting growth, development, and survival of neurons.¹⁰

In an animal model, researchers selectively injured RGCs in the eyes of mice.¹⁰ Testing showed dendritic shrinkage of injured cells when left alone, with a robust increase in dendritic arbor regrowth after topical administration of daily insulin for approximately 2 weeks. Furthermore, injury to RGCs while administering insulin yielded a 60% survival rate of these cells compared with a 14% survival rate found in injured cells not treated with insulin.¹¹ Healthy RGCs that were selectively not injured in the same eyes did not show any changes in their dendritic arbor when insulin was administered, suggesting a lack of collateral damage or ill-effect to healthy cells caused by insulin. These results exhibit evidence for neuroprotection and possible neuro-regenerative components of insulin within the central nervous system that would be promising to explore further in clinical studies.

Stem Cell-Based Therapies

Another approach to promote neuro-regeneration would be to repopulate the RGC layer. Attempts have been made at RGC transplantation and differentiation from stem cells and glial cells, and although this research is still in its infancy, recent studies have been promising.^12-14 Barriers to the success of these techniques include difficulty achieving successful migration into the RGC layer either through the inner limiting membrane or from the subretinal space and formation of functional axonal regeneration with connections to the brain; however, progress has been made on both fronts.

One recent study demonstrated disruption of the inner limiting membrane improves migration to, and distribution of stem cells within the RGC layer.¹² Soucy et al demonstrated successful migration and distribution from the subretinal space in a mouse model.¹³ Regeneration has also shown progress when used in combination with other techniques, including altering oncomodulin or decreasing cell-intrinsic axonal growth suppressors; such combined techniques have demonstrated axonal growth to the optic chiasm.¹⁴

Although research has yielded potential breakthroughs of neuro-regeneration using a variety of exogenous components, significant obstacles remain. For regeneration of RGCs to equate to functionality, for example, axons from these cells must be provided with sufficient myelination to propagate, and they must form appropriate connections to the visual pathway, including the lateral geniculate nucleus of the thalamus.¹⁵

CHANGE IS COMING

Traditionally, glaucoma management has been grounded in the modulation of IOP, a strategy that, while effective to an extent, falls short of addressing the complex and multifaceted neurodegenerative processes inherent in the condition. The focus of research on neuroprotection is to shield RGCs from damage independent of IOP. Compounds such as brimonidine, memantine, insulin, ripasudil, and others have emerged as experimental agents, signalling a paradigm shift towards targeted neuroprotection and regeneration.