Glaucoma is the second leading cause of permanent blindness in the US, and is projected to affect 6.2 million people by 2050—approximately double the number seen in 2020.1,2 This complex condition is marked by the gradual degeneration of RGCs, leading to optic neuropathy, visual field loss, and potential blindness.3
The only established treatment involves lowering intraocular pressure (IOP), yet nearly 50% of patients experience progression despite seemingly effective protocols.3 New, innovative therapies focusing on mechanisms beyond IOP control are being explored to more effectively manage disease progression.
Definition of neuroprotection
Neuroprotection seeks to maintain neural structure and function and could be pivotal in improving glaucoma management.4,5 This therapeutic approach is designed to protect neurons by boosting biochemical pathways that prevent damage or inhibit those that cause neuronal death,5 especially in chronic neurodegenerative diseases.
Overview of neuroprotection in glaucoma
In addition to IOP, apoptosis mediators, ischemic changes, ocular blood flow, and neurotoxins may play a role in glaucoma progression.6
Neuroprotective therapies target different molecules to prevent ischemia and oxidative damage, such as:
- Glutamate-induced neurotoxicity
- Nitric oxidase synthetase
- Neurotrophins
- Calcium channel receptors
- Free radicals
- Vascular insufficiency
- The rho-kinase pathway
Medications acting on these pathways may play a role in improving patient outcomes through neuroprotection.
Glaucoma neuroprotection strategies
Table 1 summarizes various neuroprotective strategies for glaucoma management.6
| Type | Drug | Neuroprotective Mechanism | Current Status |
|---|---|---|---|
| Anti-Glaucoma Medications | Beta-blockers | Inhibits retinal ischemia, causes vasodilation, and blocks glutamate release | Betaxolol preferred due to better vasodilation and increased blood flow |
| Alpha agonists | Activates neurotrophic factor, increases survival signal and decreases apoptosis, and causes vasodilation | Routine use with common local SE (follicular conjunctivitis, etc.) | |
| Prostaglandins | Blocks glutamate-induced apoptosis and hypoxic damage, and causes vasodilation | Best overall IOP effect and displays neuroprotection, especially latanoprost | |
| Carbonic anhydrase inhibitors (CAIs) | Increases ocular blood flow | Neuroprotection correlates with IOP reduction | |
| Rho-kinase inhibitors | Inhibits axonal degeneration, promotes axonal regeneration, and causes vasodilation | Promising results in studies, currently under further evaluation | |
| Antioxidants | N-methyl-D-aspartate (NMDA) antagonists | Blocks NMDA receptors and prevents apoptosis | Not effective in clinical trials |
| Citicoline | Increases synthesis of phsopholipids (protective role on RGCs) | Could be oral supplement to an ocular hypotensive agent | |
| Gingko biloba extract | Decreases endothelin-1, causing vasodilation | Potential adjuvant therapy for glaucoma progression with controlled IOP (NTG and high-tension glaucoma) | |
| Melatonin | Agomelatine shown to decrease IOP | Promising animal study results, under evaluation in human trials | |
| Crocus sativus | Increases retinal/choroidal blood flow | Promising in vivo study results | |
| Other | Calcium channel blockers | Causes vasodilation | Promising in vivo results, concerns with retinal ischemia due to decreased ocular perfusion pressure (OPP) |
| Stem cell therapy | Platelet-derived growth factor, can differentiate into RGCs | Promising initial results, debatable applicability, and ethically controversial | |
| Neurotrophins | Supports cell survival, growth, and differentiation | Currently in clinical trials | |
| Gene therapy | Enhances trabecular meshwork function, Schlemm's canal development, and preserves RGCs | Mechanism depends on targeted gene. Currently under investigation (i.e., Astellas Pharmaceuticals, etc.) |
Table 1: Adapted from Vishwaraj et al.
Anti-glaucoma medications
Beta-blockers (betaxolol, metranolol, timolol)
The neuroprotective effects of beta-blockers, especially levobetaxolol, are thought to stem from their ability to reduce sodium and calcium influx through voltage-sensitive channels, thereby inhibiting ischemia/reperfusion injury, glutamate release, and the associated NMDA receptors.6
Vishwaraj et al. noted that “Betaxolol has been demonstrated to increase blood velocity in the human optic nerve head, thus supporting the hypothesis that mediation of vasculature effects may temper ischemia-induced RGC injury.”
Alpha agonists
Brimonidine tartrate (Alphagan) appears to have neuroprotective properties independent of its ability to lower IOP.3 Hypothesized mechanisms include neurotrophic factor activation, vaso-modulation (increasing ocular blood flow), glutamate inhibition, cell-survival signal upregulation as well as apoptosis downregulation.4
Initial studies suggest the drug preserves RGC, visual fields, and contrast sensitivity in patients when it reaches effective pharmacologic concentrations in the vitreous.6 Woldemussie et al. found up to 50% more surviving RGC in brimonidine-treated eyes when compared to timolol-treated eyes in a chronic ocular hypertensive rat model.7
Further, the Low Pressure Glaucoma Treatment Study (LoGTS) found that while brimonidine and timolol had equal effects on IOP, brimonidine-treated eyes displayed less visual field progression.8 Likewise, a small randomized controlled trial found that patients treated with brimonidine had an improvement in contrast sensitivity when compared to those on timolol.9
Prostaglandin analogs
Prostaglandin analogs are a highly effective, first-line IOP-lowering glaucoma treatment with once daily dosing with minimal IOP fluctuations or systemic side effects when compared to other monotherapies.6
Additionally, latanoprost has shown a neuroprotective effect on glutamate-induced RGC death in vitro, ischemic or axotomy-induced optic neuropathy in animal models,10 and demonstrated increased optic nerve head blood circulation in rabbits, monkeys, and normal humans.11
Carbonic anhydrase inhibitors (CAIs)
CAIs control IOP by blocking the enzyme carbonic anhydrase (essential for the production of the aqueous humor), but also cause vasodilation, increasing retinal perfusion and creating a possible additive neuroprotective effect.
A study found that neuroprotective properties of dorzolamide directly correlated with the level of IOP reduction,12 so it is still unclear if CAIs provide any IOP-independent neuroprotection. Further research is needed to explore the neuroprotective potential of CAIs in greater detail.
Rho-kinase (ROCK) inhibitors
ROCK plays an important role in fundamental processes of cell migration, proliferation, and survival.3 Higher levels of rho enzyme have been detected in the optic nerve head of eyes with glaucoma compared to those of age-matched controls, supporting the theory that blocking ROCK could have neuroprotective properties.6
Both fasudil and netarsurdil have been reported to inhibit axonal degeneration, promote axonal regeneration,13 and have been found to increase ocular blood flow.14 Although the neuroprotective effects of ROCK inhibitors have been shown in the eye, additional research is needed.
Antioxidants
N-methyl-D-aspartate (NMDA) antagonists
The glutamate-based NMDA receptor activity is essential for normal neuronal function, however, excessive glutamate in the retina overstimulates NMDA receptors and is associated with glaucoma and neuronal cell death through increased calcium influx and the stimulation of proapoptotic factors.10
Memantine is a noncompetitive NMDA open-channel blocker that blocks only those NMDA receptors that are activated by glutamate without affecting their normal activity. In vitro studies showed promising results, but clinical trials did not.10
Gingko biloba extract
Ginkgo biloba extract has been used in traditional Chinese medicine for centuries due to its antioxidant and vasoactive properties. It may help reduce oxidative stress and apoptosis-related optic nerve head damage.
Research by Malishevskaia and Dolgova demonstrated a notable reduction of endothelin-1, resulting in vasodilation in patients receiving gingko biloba extract, highlighting its significant antioxidant and antihypoxic effects.15
Melatonin
Melatonin is not only known for its role in sleep regulation, but also for antioxidant and anti-scavenging properties. These attributes could potentially offer beneficial effects in terms of antioxidant and ocular hypotensive properties.6
As a result, synthetic analogs and melatonin receptor agonists are being studied. Notably, agomelatine has demonstrated both ocular IOP lowering and antioxidant effects in human and animal trials.16,17
Crocus sativus (saffron)
Saffron is rich in the carotenoids crocin and crocetin. Crocin is believed to enhance blood flow in the retina and the choroid through vasodilation in vivo, which may aid in the recovery of retinal function recovery after an increase in IOP.6,18
Other therapies
Calcium channel blockers (CCBs)
Beyond their primary use of treating angina pectoris, hypertension, and arrhythmias, CCBs have shown clinical neuroprotective potential in open-angle glaucoma.3
CCBs (e.g., lomerizine and nilvadipine) dilate isolated ocular vessels and increased ocular blood flow, however, associated systemic hypotension is a concern as it could exacerbate retinal ischemia due to decreased OPP.6
Stem cell therapy
Stem cell therapy has been implicated in neuroprotection and neuroregeneration and is being explored through ongoing research and clinical trials, particularly mesenchymal and human embryonic stem cells.3,6
Mesenchymal stromal cells (MSCs)
MSCs have been associated with platelet-derived growth factor, however, the intravitreal injection is associated with adverse effects, such as reactive gliosis, vitreous clumping, and epiretinal membrane thickening.6
Human embryonic stem cells (hESCs)
Of note, hESCs have the capacity to differentiate into RGCs and have been successfully integrated in host retinas,19 however, this technology is ethically controversial and scientifically challenging.
Bone marrow-derived mesenchymal stem cell (BMSC)
Exosomes are extracellular vesicles whose proteins, microRNAs (miRNAs), and lipids are involved in various processes that suggest their potential for neuroprotection in glaucoma, such as nerve injury and repair, vascular regeneration, and immune response.
Mead and Tomarev found that bone marrow-derived mesenchymal stem cell (BMSC) exosomes significantly enhanced retinal ganglion cell (RGC) survival and promoted axon regeneration, while partially preventing RGC axonal loss and dysfunction through a miRNA mechanism.20
Neurotrophins
Ciliary neurotrophic factor (CNTF)
CNTF is a hypothalamic neuropeptide that Neurotech Pharmaceuticals is investigating for neuroprotection properties in glaucoma.3 Phase 1 clinical trial revealed glaucomatous eyes with CNTF-secreting implants retained better visual acuity, contrast sensitivity, field of vision, and RNFL thickness than the control eye.21 Phase II, focusing on sustained CNTF release, is currently underway.21
Recombinant human nerve growth factor (rhNGF)
Nerve growth factor (NGF) is a naturally occurring human protein that supports neuronal differentiation, survival, and axonal growth throughout the nervous system.3 Recent research showed lower NGF levels in early and moderate glaucoma patients compared to healthy controls.22
rhNGF is a therapeutic variant with a proven safety and efficacy profile, is currently used topically for neurotrophic keratitis, and is being investigated for glaucoma.23 The NGF-Glaucoma trial aims to assess the safety and tolerability of rhNGF ophthalmic solution as well as structural and functional evaluations using optical coherence tomography (OCT), visual field, and electroretinography (ERG).
No adverse effects were reported, and both structural and functional measures exhibited trends that, while not statistically significant, favored rhNGF.23
Gene therapy
Myocilin (MYOC) gene
Primary open-angle glaucoma (POAG) is often associated with changes in the MYOC gene, which encodes for the protein MYOC primarily found in the ocular trabecular meshwork (TM).24 Abnormal MYOC accumulates in the TM, causing stress and dysfunction, increasing IOP.
Jain et al. demonstrated that by genetically inhibiting mutant MYOC expression in mice models, they were able to reduce IOP and minimize glaucomatous retinal damage.25
Tunica interna endothelial cell kinase (TEK)
TEK is an angiopoietin receptor involved in Schlemm’s canal development. Its disruption is associated with congenital glaucoma. It is hypothesized that gain-of-function mutations in TEK may have potential value in gene therapy.
Conclusion
While current treatments can slow glaucoma progression, their impact is primarily limited to controlling IOP. Neuroprotective therapies hold great promise for advancing disease management, but face notable challenges.
Evidence supporting their effectiveness is still scarce and direct comparisons with conventional treatments are needed to validate their benefits and evaluate their role in both managing and preventing glaucoma, especially in individuals with genetic predispositions.
