Glaucoma is an optic neuropathy characterized by progressive loss of RGCs and visual field defects, and is the leading cause of irreversible blindness worldwide2). IOP is the only modifiable risk factor, but despite IOP reduction, glaucomatous damage progresses in about 50% of patients2).
Neuroprotection is defined as “a therapeutic approach aimed at directly preventing or suppressing neuronal damage”11, 12). Although multiple compounds have shown RGC protective effects in animal models, no drug has yet reached sufficient evidence in human glaucoma11, 12).
The Glaucoma Clinical Practice Guidelines (5th edition) cite a systematic review by Sena et al. stating that at least 4 years of observation are needed to clinically judge neuroprotective effects, and that further research is needed to establish evidence10).
QWhich is more important: neuroprotection or IOP-lowering treatment?
A
IOP reduction is the only established glaucoma treatment and is the highest priority10, 11). Neuroprotection is not a substitute for IOP reduction but is being researched as an adjunctive approach. Relying solely on neuroprotective strategies and neglecting established IOP-lowering therapy is not recommended11).
2. Pathological Conditions Targeted by Neuroprotection
In glaucoma, RGCs, the final output neurons of the retina, are selectively lost8). Other retinal neurons (amacrine cells, photoreceptors, etc.) are relatively spared. Visual field defects are the functional expression of RGC loss; traditionally, peripheral visual field impairment has been emphasized, but recent studies have revealed that macular GCL thinning occurs from early stages.
RGC death is multifactorial and involves multiple pathways9). The main mechanisms and corresponding neuroprotective targets are described below.
Primary injury mechanisms
Glutamate excitotoxicity: Excessive glutamate activates NMDA receptors, inducing RGC death via Ca²⁺ influx2, 9)
Oxidative stress: Overproduction of reactive oxygen species (ROS). In primary open-angle glaucoma, aqueous humor levels of water-soluble antioxidants (glutathione, ascorbic acid) are decreased, and serum malondialdehyde is approximately doubled6)
Mitochondrial dysfunction: RGC axons at the lamina cribrosa are unmyelinated and have high energy demands. Decreased mitochondrial complex I activity and reduced ATP synthesis have been reported6)
Secondary injury mechanisms
Axonal transport impairment: Anterograde and retrograde axonal transport is blocked at the lamina cribrosa of the optic nerve head, leading to apoptosis due to neurotrophic factor deprivation8, 9)
Neuroinflammation: Involves activation of microglia and astrocytes, complement cascade activation, and release of inflammatory cytokines such as TNF-α and IL-1β5, 9)
Apoptosis: Cell death pathway mediated by the JNK stress response pathway, Bcl-2 family, and caspase cascade. RGC death occurs mainly via apoptosis9)
An ideal neuroprotective agent must meet the following conditions9): (1) have specific target receptors in the retina and optic nerve; (2) experimentally demonstrate enhanced neuronal resistance; (3) reach therapeutic concentrations in target tissues; and (4) show neuroprotective effects in prospective randomized clinical trials. Currently, no drug satisfies condition (4).
Brimonidine is an alpha-2 adrenergic receptor agonist widely used as an intraocular pressure (IOP)-lowering agent. Animal studies have reported that it increases retinal ganglion cell (RGC) survival approximately 1.5 times more than timolol, independent of IOP reduction2, 7).
Proposed neuroprotective mechanisms2, 5):
Increased expression of neurotrophic factors (BDNF, FGF) and their receptors
Suppression of Bax (pro-apoptotic factor) and increased expression of Bcl-2 (anti-apoptotic factor)
Inhibition of glutamate accumulation
Reduction of amyloid beta
Improvement of ocular blood flow
Low-pressure Glaucoma Treatment Study (LoGTS): A multicenter, double-masked RCT involving 178 patients with low-tension glaucoma10, 11). Brimonidine tartrate 0.2% was compared with timolol maleate 0.5%. Over 48 months of follow-up, IOP reduction was equivalent, but visual field progression was significantly less in the brimonidine group (9.1%) than in the timolol group (39.2%)7, 11). However, dropout rates were 55% in the brimonidine group and about 30% in the timolol group, with most dropouts in the brimonidine group due to ocular allergy. This high dropout rate introduced bias, and definitive conclusions could not be drawn10, 11).
QDoes brimonidine have neuroprotective effects beyond IOP lowering?
A
Animal models have shown IOP-independent RGC protective effects2, 7). In the LoGTS trial, despite equivalent IOP reduction to timolol, the brimonidine group had significantly less visual field progression10, 11). However, due to high dropout rates, the evidence is considered insufficient10).
Memantine is a non-competitive NMDA receptor antagonist that suppresses glutamate excitotoxicity. Animal models have shown RGC protective effects 2, 7).
However, in two Phase III multicenter RCTs involving 2,298 patients with open-angle glaucoma (memantine 20 mg group, 10 mg group, placebo group, 48-month follow-up), no consistent suppression of glaucoma progression was confirmed 2, 7, 10).
Citicoline (cytidine 5’-diphosphocholine) is an endogenous compound that plays an important role in maintaining cell membrane phospholipids 1, 2, 7).
Routes of administration and clinical evidence:
Intramuscular injection: 1 g/day for 10 days improved visual fields in all patients with primary open-angle glaucoma. The effect persisted for 3 months, and maintenance for over 10 years with repeated administration every 6 months has been reported 2)
Oral administration: 500 mg/day (4 months on, 2 months off cycle) for 2 years significantly reduced the visual field progression rate to -0.15 ± 0.3 dB per year 2). Improvements in PERG and VEP have also been reported
Eye drops: Topical administration also showed improvements in PERG and VEP, but there are concerns about side effects due to penetration into the vitreous body2)
In an RCT of citicoline eye drops in 80 patients with open-angle glaucoma showing progression despite intraocular pressure control, progression was significantly suppressed over 3 years as assessed by Humphrey 10-2 and OCTRNFL thickness evaluation 10). In Europe, citicoline is approved as a special medical food 11).
QIs citicoline effective for glaucoma?
A
Multiple clinical studies have reported improvements in PERG and VEP and protection of RNFL with citicoline 1, 2). Efficacy has been observed with oral, intramuscular, and topical routes, but some reports indicate that more than one year of treatment may be necessary for significant effects to appear 2). Large-scale Phase III trials are currently underway 2).
Nicotinamide (vitamin B3) is a major precursor of NAD+. NAD+ is essential for mitochondrial energy production, and it has been shown that NAD+ levels in neurons decrease with aging and IOP stress 6).
In the DBA/2J mouse glaucoma model, high-dose nicotinamide supplementation prevented detectable glaucoma in 93% of eyes 6). In a clinical trial (crossover RCT of 57 patients), oral nicotinamide 1.5–3 g/day for 3 months improved PhNR amplitude by 14.8% (p=0.02), and visual fields improved by 1 dB or more in 27% of patients 1, 2, 4).
Currently, the TGNT trial involving 660 patients with open-angle glaucoma and a large-scale RCT of nicotinamide plus pyruvate are underway 2, 4). In the combination trial of nicotinamide and pyruvate, the median number of visual field improvement points was significantly higher in the treatment group (15 points) compared to the placebo group (7 points) (p=0.005) 4).
Brain-derived neurotrophic factor promotes RGC survival via the TrkB receptor 8).
BDNF levels in aqueous humor, tears, and serum of glaucoma patients are significantly lower than in healthy individuals, suggesting its potential as a biomarker8).
In animal models, intravitreal administration of BDNF has shown RGC protective effects, but its short half-life requires repeated administration 8).
Gene therapy using an AAV vector enabling dual overexpression of BDNF and TrkB has been developed, and a Phase I/IIa trial is planned 2).
CNTF and NGF
Ciliary neurotrophic factor (CNTF): A Phase II trial of the NT-501 device, which continuously releases CNTF from genetically modified cells, is ongoing. In Phase I, the treated eyes showed less decline in visual acuity and RNFL thickness compared to control eyes 2).
Nerve growth factor (NGF): RGC protective effects in animal models. A Phase Ib trial of topical rhNGF showed no serious adverse events and a favorable trend in structural and functional measures for rhNGF, but did not reach statistical significance 2).
Ginkgo biloba extract (GBE) has antioxidant and vasoregulatory effects 1, 2, 7). In a crossover RCT of 27 NTG patients, 4 weeks of GBE 40 mg three times daily significantly improved visual field MD from -11.40±3.27 to -8.78±2.56 dB (p<0.001) 1, 2). A 4-year longitudinal study also reported significant visual field improvement in the GBE-treated group 2).
However, another crossover trial in a Chinese NTG cohort found no improvement, and results are inconsistent 2). GBE is contraindicated in patients using anticoagulants 11).
5-year study showed suppression of visual field progression10)
Regarding calcium channel blockers, the Glaucoma Practice Guidelines (5th edition) mention that a study of nilvadipine in 33 patients with normal-tension glaucoma reported improved ocular blood flow as measured by laser Doppler flowmetry10). For cassis anthocyanin, a 2-year randomized double-masked trial reported significant suppression of visual field progression10).
In stem cell therapy, mesenchymal stem cells (MSCs) are attracting attention. MSCs secrete neurotrophic factors such as PDGF and BDNF5). However, reactive gliosis, vitreous opacity, and epiretinal membrane formation have been reported after intravitreal injection2), and further research is needed for clinical application. MSC-derived exosomes promote RGC survival and axonal regeneration in a miRNA-dependent manner and are being studied as an alternative to reduce the risks of cell transplantation2).
In gene therapy, BDNF+TrkB double-overexpressing AAV vectors 2), introduction of loss-of-function mutations in the myocilin gene 2), and gain-of-function mutations in the TEK receptor 2) are being studied.
At the lamina cribrosa of the optic nerve head, RGC axons experience mechanical stress. Circumferential stress (hoop stress) due to IOP and the difference between IOP and optic nerve tissue pressure (trans-LC pressure difference) are the main physical factors 9).
The JNK stress response pathway plays a central role in signaling RGC death. Increased expression of c-Jun has been confirmed in RGCs and astrocytes in glaucoma models, and JNK2/JNK3 double-deficient mice show improved RGC survival 9). It has been most conclusively shown that kinases upstream of JNK transmit damage signals.
Blockade of retrograde axonal transport occurs at the lamina cribrosa, interrupting the supply of neurotrophic factors (especially BDNF) to the cell body, thereby triggering apoptosis8). Axonal mitochondrial dysfunction is also involved, and unmyelinated fibers at the lamina cribrosa are particularly vulnerable due to their high energy demand 6).
NAD+ is an essential coenzyme for the mitochondrial electron transport chain 6). Aging and IOP stress reduce the expression of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), leading to NAD+ depletion in neurons 6). In DBA/2J mice, overexpression of NMNAT1 prevented optic neuropathy in over 70% of eyes 6). In lymphoblasts from primary open-angle glaucoma patients, decreased mitochondrial complex I enzyme activity and reduced ATP synthesis have been confirmed 6).
Microglial activation and release of TNF-α and IL-1β promote RGC death 5, 9). Complement cascade activation is also involved, and CR2-Crry gene therapy has been reported to reduce RGC degeneration 5). The Fas ligand antagonist (ONL1204) decreased gliosis, macrophage infiltration, and inflammatory cytokines, and suppressed RGC death 5).
Petriti et al. (2021) reviewed that NAD+ depletion is a central mechanism of glaucomatous neurodegeneration and that nicotinamide supplementation is a promising therapeutic target 6). In the DBA/2J mouse model, high-dose nicotinamide prevented glaucoma in 93% of eyes, and NMNAT1 overexpression prevented optic neuropathy in over 70% of eyes. In human clinical trials, PhNR amplitude improvement was confirmed at doses of 1.5–3 g/day.
Martucci et al. (2025) reviewed the efficacy of multi-target combination therapies such as citicoline + homotaurine, nicotinamide + pyruvate, and CoQ10 + vitamin B3 3). Neuroprotective candidates that had limited efficacy as monotherapies have been reported to improve RGC electrophysiological indicators, visual field parameters, and QOL when administered as fixed-dose combinations targeting complementary pathways.
Liu and Ang (2025) proposed the NP-10 neuroprotection system that systematically covers 10 mechanisms (pressure-related, vascular, cellular dysfunction, functional deficits) 4). They organized evidence for individual nutraceuticals by mechanism, showing the roles of saffron (IOP lowering), Ginkgo biloba + bilberry (vascular), nicotinamide + pyruvate (mitochondrial), and citicoline (functional improvement).
Skopiski et al. (2021) reviewed that Rho kinase inhibitors (ripasudil, netarsudil) promote neurite outgrowth and axonal regeneration in addition to lowering IOP5). Additive protective effects were observed in combination with brimonidine. Furthermore, immunomodulatory approaches such as TLR4 inhibitors, phosphodiesterase-4 inhibitors (ibudilast), complement inhibition, Fas ligand antagonists, and TNF-α inhibitors (etanercept) have shown RGC protection in animal models.
QWhat are the main ongoing clinical trials?
A
Ongoing or planned trials include a large RCT of nicotinamide (TGNT trial, 660 patients with open-angle glaucoma, expected completion in 2026) 2), a Phase III trial of citicoline eye drops 2), a Phase II trial of the CNTF-releasing NT-501 device 2), the next phase of a Phase Ib trial of rhNGF eye drops 2), and a Phase I/IIa trial of AAV with dual BDNF+TrkB overexpression 2).
D’Angelo A, Vitiello L, Lixi F, et al. Optic Nerve Neuroprotection in Glaucoma: A Narrative Review. J Clin Med. 2024;13(8):2214.
Wang L-H, Huang C-H, Lin I-C. Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies. Pharmaceuticals. 2024;17(10):1261.
Martucci A, Cesareo M, Pinazo-Durán MD, et al. Next-Gen Neuroprotection in Glaucoma: Synergistic Molecules for Targeted Therapy. J Clin Med. 2025;14(17):6145.
Liu Z, Ang GS. Nutraceuticals and Neuroprotection for Glaucoma—Introducing the NP-10 System. Ther Adv Ophthalmol. 2025;17:1-11.
Skopiski P, Radomska-Leśniewska DM, Izdebska J, et al. New Perspectives of Immunomodulation and Neuroprotection in Glaucoma. Cent Eur J Immunol. 2021;46(1):105-110.
Petriti B, Williams PA, Lascaratos G, et al. Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target. Cells. 2021;10(6):1402.
Vishwaraj CR, Kavitha S, Venkatesh R, et al. Neuroprotection in Glaucoma. Indian J Ophthalmol. 2022;70(2):380-385.
Lambuk L, Mohd Lazaldin MA, Ahmad S, et al. Brain-Derived Neurotrophic Factor-Mediated Neuroprotection in Glaucoma: A Review of Current State. Front Pharmacol. 2022;13:875662.
Kuo C-Y, Liu CJ-L. Neuroprotection in Glaucoma: Basic Aspects and Clinical Relevance. J Pers Med. 2022;12(11):1884.
日本緑内障学会. 緑内障診療ガイドライン（第5版）. 日眼会誌. 2022.
European Glaucoma Society. European Glaucoma Society Terminology and Guidelines for Glaucoma, 6th Edition. Br J Ophthalmol. 2025.
European Glaucoma Society. European Glaucoma Society Terminology and Guidelines for Glaucoma, 5th Edition. Savona: PubliComm; 2020.
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