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Abstract

Glaucoma, a leading global cause of irreversible blindness, often progresses despite adequate intraocular pressure (IOP) control, highlighting a crucial unmet need for neuroprotective strategies that directly promote retinal ganglion cell survival. In addition, the glaucoma standard of care is often reactive, initiating only on measurable structural or functional loss and lacking in structured, proactive approach to neuroprotection. This review introduces the NP-10 System, a novel conceptual framework designed to systematically address 10 diverse and interrelated neuroprotective mechanisms implicated in glaucomatous neurodegeneration. Broadly, these can be categorized as pressure-related factors (direct IOP and psychological stress), vascular factors (encompassing vascular dysregulation and homocysteine-related endothelial dysfunction), cellular dysfunctions (mitochondrial dysfunction, glycolysis impairment, oxidative stress, and chronic inflammation), and functional deficits (macular pigment deficiency and impaired axonal function). Specific nutraceutical interventions, including saffron, French maritime pine, bilberry, palmitoylethanolamide, nicotinamide, methylfolate, methylcobalamin, macular carotenoids, Ginkgo biloba, pyruvate, and citicoline, may target multiple mechanisms to reduce IOP, modulate stress, improve ocular perfusion, enhance cellular bioenergetics, provide antioxidant and anti-inflammatory benefits, augment macular pigment, and improve visual function in glaucoma. With promising emerging evidence for neuroprotection, the NP-10 System provides a scaffold for future large, randomized trials to establish clinical efficacy, optimize formulations, and clarify safety profiles of these nutraceuticals, paving the way for integrating targeted nutritional support into proactive glaucoma care.

Plain language summary

Protecting your vision in glaucoma: a new 10-point approach (the NP-10 System)

Glaucoma is a leading cause of permanent blindness, and damages the eye’s nerve cells (retinal ganglion cells, or RGCs) due to factors like high eye pressure. However, even when eye pressure is well controlled, sight can still worsen, suggesting that other factors are involved.

In addition, glaucoma treatment currently often only starts after permanent damage is detected. There is no framework in place to proactively protect these RGCs before damage occurs.

In light of these considerations, this article introduces the NP-10 System, a new framework that looks at ten different ways glaucoma can harm the eye’s RGCs, and ways to address them proactively. These include direct eye pressure, stress, poor blood flow, problems with the cell’s energy and inflammation, and specific visual function issues.

Certain natural substances from foods (called nutraceuticals), like saffron, bilberry, and some vitamins, show promise in proactively improving these areas. Early findings are encouraging, but more research through large studies is needed to confirm their benefits and safety.

The NP-10 System helps guide this research and offers a way for doctors to think about more complete and proactive glaucoma care.

Keywords

glaucoma neuroprotection nutraceuticals

Introduction

Poised to affect over 110 million people by 2040 and incur substantial healthcare costs, glaucoma represents a leading global cause of irreversible blindness and a major clinical and public health challenge.^1,2 Management traditionally centers around lowering intraocular pressure (IOP)—the most established modifiable risk factor. However, disease does not infrequently progresses despite adequate IOP control, emphasizing the limitations of treatments that are solely pressure-centric in the context of a multifaceted pathophysiology. There is an unmet need for strategies that directly protect retinal ganglion cells (RGCs) from degeneration and promote their survival, independent of, or complementary to, IOP control—a concept known as neuroprotection.

Current glaucoma standard of care frequently involves treatment initiation after measurable structural or functional loss—a reactive approach. Proactive approaches are increasingly recognized, with lifestyle improvements in domains such as diet, exercise, and sleep used to mitigate glaucoma risk and progression while supporting general health.³ A structured, proactive approach to neuroprotection is lacking.

To address this gap, we introduce the NP-10 System (Figure 1), an original conceptual framework designed to systematically address ten diverse and interrelated neuroprotective mechanisms implicated in glaucomatous neurodegeneration. These can be broadly categorized as pressure-related factors, vascular factors, cellular dysfunctions, and functional deficits.

Pressure-related factors include the direct mechanical effect of elevated IOP and the role of psychological stress in influencing IOP.

The vascular factors encompass vascular dysregulation and homocysteine-related endothelial dysfunction.

Cellular dysfunctions cover mitochondrial dysfunction, glycolysis impairment, oxidative stress, and chronic inflammation.

Functional deficits involve macular pigment deficiency and impaired axonal function.

Figure 1.

The NP-10 System.

Identifying and defining these diverse pathophysiological mechanisms provides systematic strategies for targeted interventions. Nutraceuticals—defined as food-derived substances offering health benefits beyond nutrition alone—emerge as a promising approach. Growing patient interest in complementary therapies highlights both the relevance of nutraceuticals in medicine and the pressing need for rigorous scientific validation of their clinical utility. Certain vitamins, minerals, and biologically active compounds may complement conventional therapies through offsetting these deleterious processes. This review explores the evidence behind the components of the NP-10 System in glaucoma and discusses the potential therapeutic role of targeted nutraceutical interventions within a broader neuroprotective paradigm.

Methods

This narrative review searched PubMed and Google Scholar from inception to May 2025. Search terms included “glaucoma,” “neuroprotection,” “retinal ganglion cell,” combined with terms for each component of the NP-10 System and relevant “nutraceuticals,” such as “saffron,” “nicotinamide,” “Ginkgo biloba,” “French maritime pine,” “bilberry,” “palmitoylethanolamide,” “carotenoid,” “homocysteine,” “pyruvate,” “magnesium citrate,” “vitamin,” “grape seed,” and “citicoline,” among others. The selection of evidence was limited to nutraceutical interventions and guided by relevance to the ten mechanisms outlined in the NP-10 framework. Human clinical trials were prioritized where available, and preclinical evidence was included to provide mechanistic insights.

Pressure-related factors

Intraocular pressure

The foremost modifiable risk factor in glaucoma is IOP. Certain nutraceuticals may offer IOP-lowering benefits that complement conventional therapy.

Saffron (Crocus sativus), a spice known for a panoply of systemic health benefits from cardiovascular and metabolic diseases, mental health, to oncology,⁴ demonstrates ocular benefits in age-related macular degeneration⁵ and IOP modulation in glaucoma. A small, randomized pilot study of 34 participants (34 eyes) over 50 years of age with mild to moderate primary open-angle glaucoma (POAG), stable on topical timolol and dorzolamide, investigated the effect of 30 mg per day of oral aqueous saffron extract versus placebo.⁶ A statistically significant IOP reduction was observed in those with saffron supplementation at 3 weeks (10.9 ± 3.3 mmHg vs 13.5 ± 2.3 mmHg; p = 0.013) and 4 weeks (10.6 ± 3.0 vs 13.8 ± 2.2 mmHg; p = 0.001) compared to control; this benefit ceased upon saffron discontinuation.

French maritime pine (Pinus pinaster) bark and bilberry (Vaccinium myrtillus) fruit carry anti-inflammatory and antioxidant properties,^7,8 benefit dry eye disease,⁹ and lower IOP. A prospective, single-arm, pre-post intervention study of 18 participants (29 eyes) with POAG found that a 4-week oral course (dosed at 40 mg/90 mg, respectively) led to an average IOP reduction of 1.5 mmHg (15.7 ± 1.9 mmHg vs 17.2 ± 2.3 mmHg; p = 0.005).¹⁰ Whether these effects are mediated through their anti-inflammatory and antioxidative capacities or via changes in aqueous humor dynamics is actively investigated.^11–13

Palmitoylethanolamide (PEA), a fatty acid amide found endogenously as well as in dietary sources including egg yolk, nuts, and legumes, has also shown IOP-lowering potential through potential interactions with the endocannabinoid system.^14,15 A systematic review and meta-analysis of six randomized trials with 199 participants found that daily supplementation with 600 mg of PEA resulted in a 1.33 mmHg (95% confidence interval (CI) 0.85–1.86; p < 0.001) greater reduction in IOP than placebo.¹⁵ Although topical PEA did not lower IOP, it yielded significant improvements in ocular surface inflammation, including that secondary to chronic IOP-lowering eye drops.^14,16

Psychological stress

Psychological stress can engender transient or sustained IOP increases. Randomized studies have demonstrated that standardized psychological stress tests can lead to acute IOP elevations of approximately 4 mmHg in glaucoma patients.¹⁷ Conversely, stress reduction interventions can decrease IOP—by 6 mmHg after 21 days of mindfulness meditation, for example.¹⁸ The mechanisms behind these benefits may encompass cortisol reduction, enhanced neuro-oxygenation, neurotrophins upregulation, and parasympathetic reinforcement.^19–22 In turn, the oxidative stress, glutamate excitotoxicity, and proinflammatory cascades implicated in glaucomatous neurodegeneration may be attenuated.^19–22

In this context, nutraceuticals with psychomodulatory effects may benefit glaucoma management. Saffron, discussed already for its ability to lower IOP, also modulates anxiety and mood. A randomized trial involving 73 participants found that 30 mg of oral saffron extract daily for 56 days led to greater reductions in subjective low mood (p = 0.05) and improved social relationship scores (p = 0.007) compared to placebo.²³ Furthermore, oral saffron supplementation for 4 weeks (14 or 28 mg per day) has been shown to improve sleep quality,²⁴ potentially indirectly contributing to stress relief and boosting overall well-being.

Macular carotenoids—lutein, zeaxanthin, and meso-zeaxanthin—have also shown chronic mental stress reduction effects beyond their well-known role in age-related macular degeneration. A randomized trial with 59 participants found that psychological stress was significantly improved following 6 months of oral supplementation compared to placebo (p < 0.05).²⁵ Additional benefits were decreased serum cortisol and improved emotional and physical health (p < 0.05 for both). All benefits were sustained or enhanced at 12 months.

Vascular factors

Beyond mechanical damage to RGC axons due to elevated IOP, ocular blood flow is essential for RGC survival.²⁶ Arising from vascular dysregulation and endothelial dysfunction, ocular perfusion deficits can limit optic nerve oxygenation and nutrition.

Homocysteine, one-carbon metabolism, and endothelial dysfunction

Hyperhomocysteinaemia is associated with endothelial dysfunction,²⁷ which not only impairs vascular integrity and functionality, but may also be a pathogenic, though not causative, marker of dysregulated one-carbon metabolism in some glaucomas.²⁸ A cross-sectional, prospective study of 79 participants noted that pseudoexfoliation syndrome and pseudoexfoliation glaucoma were both associated with elevated homocysteine compared to control (p = 0.033; p = 0.023, respectively), while POAG was not (p = 0.996).²⁹ Similarly, multivariable logistic regression analyses identified hyperhomocysteinaemia concentration as a significant risk factor for pseudoexfoliation syndrome (odds ratio (OR) per 1 µmol/L increase 2.05, 95% CI 1.19–3.52) and pseudoexfoliation glaucoma (OR per 1 µmol/L increase 1.36, 95% CI 1.00–1.85), but not for POAG.²⁹ The endothelial injury seen in hyperhomocysteinaemia may be a mechanistic link between pseudoexfoliation and the increased propensity for vascular disease observed in these patients.³⁰

Homocysteine and one-carbon metabolism require folate and vitamin B12.³¹ Both these cofactors become increasingly deficient with age and dietary malabsorption—from about 5% in those aged 65–74 years to over 10% among those aged 75 years or older—and may benefit from supplementation.³² In mice, supplementation with essential cofactors and precursors of one-carbon metabolism—vitamins B6, B9, B12, and choline—demonstrates neuroprotection in acute glaucoma models and conveys structural and electroretinographic visual benefits in chronic models.²⁸

In humans, supplementing with bioactive forms such as methylfolate and methylcobalamin is preferred due to superior bioavailability and immediate metabolic utility, ameliorating endothelial dysfunction and improving microvascular perfusion.³³ A large national prospective cohort study, following 78,980 women and 41,221 men for over 20 years, suggested a linear trend toward a reduced risk of pseudoexfoliation glaucoma with higher folate intake (p = 0.02), which was, notably, driven by supplemental folate intake (p = 0.03) rather than dietary folate alone.³⁴

Vascular regulation

Ginkgo biloba and bilberry extracts exert direct vasomodulatory effects that may reduce vascular resistance and improve perfusion within crucial retinal and retrobulbar vascular territories. This may be especially pertinent in normal-tension glaucoma (NTG), given the relatively lesser importance of elevated IOP in these populations.^35,36 A randomized crossover trial of 27 NTG patients with visual field deficits investigated the effects of oral administration of 40 mg Ginkgo biloba extract three times a day for 4 weeks, with significant improvements in visual field indices.³⁷ The mean deviation improved from a baseline of 11.40 ± 3.27 dB to 8.78 ± 2.56 dB (p < 0.001), and the corrected pattern standard deviation improved from 10.93 ± 2.12 dB to 8.13 ± 2.12 dB (p < 0.001). Importantly, there were no significant changes in IOP or systemic haemodynamics.

Further supporting these observations, long-term data from a retrospective analysis of 332 participants with NTG demonstrated a mean deviation improvement from −5.25 ± 6.13 to −4.31 ± 5.60 (p = 0.002) in those treated with Ginkgo biloba extract over 24 months, while those without supplementation experienced no change (p = 0.725).³⁸ The same study also found that supplementation with bilberry anthocyanins similarly improved mean deviation from −6.44 ± 7.05 to −5.34 ± 6.42 (p = 0.001), demonstrating the potential benefit of targeting vascular compromise with specific nutraceuticals to maintain and even improve visual function.

Cellular dysfunctions

Underpinning direct pressure-related and vascular insults in glaucomatous pathophysiology is a complex interplay of RGC cellular dysfunctions. These intrinsic vulnerabilities of mitochondrial failure, bioenergetic impairment, and the deleterious tandem of oxidative stress and chronic inflammation are key targets within the NP-10 framework.

Mitochondrial dysfunction

With high energy requirements dictated by continuous action potential generation across extensive unmyelinated axons, RGC mitochondrial dysfunction can lead to an energy crisis, which culminates in apoptosis.³⁹ One promising agent that may counteract this bioenergetic deficit and support mitochondrial respiration and adenosine triphosphate (ATP) production in glaucoma is the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide (vitamin B3).

A randomized crossover trial of 57 participants with glaucoma found that oral nicotinamide supplementation (1.5 g per day for 6 weeks, then 3 g per day for 6 weeks) led to significant improvements in electroretinographic markers of inner retinal function.⁴⁰ Specifically, the saturated photopic negative response amplitude improved by 14.8% (95% CI 2.8%–26.9%; p = 0.02) with nicotinamide compared to 5.2% (95% CI 4.2–14.6%; p = 0.27) with placebo, while the photopic negative response/b-wave amplitude ratio improved by 12.6% (95% CI 5.0%–20.2%; p = 0.002) following nicotinamide and 3.6% (95% CI −3.4% to 10.5%; p = 0.30) on placebo. Nicotinamide also contributed to a trend toward improved visual field mean deviation: 27% of participants improved by ⩾1 dB on nicotinamide and fewer deteriorated (4%) compared to placebo (p = 0.02).⁴⁰

Through reinforcing mitochondrial function, nicotinamide supplementation enhanced RGC survival and inner retinal function; ongoing studies are underway to elucidate long-term neuroprotective efficacy. Complementing this finding, preclinical work in glaucomatous mouse models suggests that grape seed proanthocyanidins can also alleviate mitochondrial dysfunction by regulating mitochondrial reactive oxygen species.⁴¹

Glycolysis impairment

Impairment of glycolysis can exacerbate cellular bioenergetic deficits in times of metabolic stress and increase their susceptibility to degeneration. Pyruvate, the central glycolytic metabolite and mitochondrial fuel, has shown neuroprotective effects for RGCs in glaucoma mouse models.⁴² Supplementation with pyruvate in humans may also support RGC bioenergetics, in combination with other nutraceuticals such as nicotinamide.

A randomized trial involving 32 patients with open-angle glaucoma found that a combination of oral nicotinamide (1000–3000 mg per day) and pyruvate (1500–3000 mg per day) over a median follow-up of 2.2 months resulted in a significantly higher number of visual field test location improvements compared to placebo (median 15 (IQR 6–25) vs 7 (IQR 6–11); p = 0.005).⁴³ The pattern standard deviation rate of change also suggested improvement with supplementation (median −0.06 dB per week) compared with placebo (median 0.02 dB per week; p = 0.02).⁴³

Another randomized trial with 30 participants found that 1 month of 300 mg daily oral magnesium citrate supplementation improved both visual field mean deviation (−3.7 ± 1.9 to −2.5 ± 1.8; p = 0.027) and pattern standard deviation (3.6 ± 2.3 to 2.8 ± 2.6; p = 0.04) without affecting ocular blood flow, leading to the authors postulating other mechanisms for neuroprotection at play.⁴⁴ Magnesium is a key co-factor in glycolysis, while citrate is of fundamental importance in the citric acid cycle; bolstering both may circumvent mitochondrial defects, help fortify energy supply to stressed RGCs.

Oxidative stress and chronic inflammation

Oxidative stress—the imbalance between the reactive oxygen species (ROS) generation and cellular antioxidant capacity—and chronic, low-grade inflammation, potentiate one another to promote a hostile microenvironment that aggravates RGC demise. In addition, mitochondrial dysfunction is a major source of ROS, further underscoring the integration of these cellular dysfunctions.

Interventions that can dampen oxidative stress and inflammatory responses are of considerable interest. A population-based study of 6,128 participants from the National Health and Nutrition Examination Survey database found that increased dietary antioxidant intake—a composite of vitamins A, C, E, zinc, selenium, and magnesium—was associated with decreased odds of self-reported glaucoma in US adults 40 years and older (OR 0.94, 95% CI 0.90–0.99 per unit increase in antioxidant intake; p = 0.02).⁴⁵

Several nutraceuticals, some already discussed for their benefits on IOP or vascular function, possess potent antioxidant and anti-inflammatory properties. Saffron, for instance, is well known for its antioxidant benefits, in addition to its IOP-modulating and psycho-modulatory effects previously discussed.⁴

Similarly, Ginkgo biloba and bilberry extracts, previously examined for vasomodulatory effects,^37,38 also exert considerable antioxidant and anti-inflammatory actions.^38,46–48 Ginkgo biloba extract significantly enhances RGC survival following oxidative stress in vitro (p < 0.001).⁴⁶ Rat models of hypoxic optic nerve injury demonstrate significant RGC density improvements following 100 or 250 mg per kg systemic Ginkgo biloba extract supplementation (p < 0.01), an effect attributable to its antioxidant and anti-apoptotic properties.^46,48 Bilberry extract, rich in anthocyanin antioxidants, further mitigates cellular stress. Daily oral bilberry extract (100 or 500 mg per kg) significantly increased RGC survival in mouse models of optic nerve crush through endoplasmic reticulum stress reduction and reduced proapoptotic retinal gene expression.⁴⁷

A variety of grape seed components, such as linoleic acid, vitamin E, phytosterols, catechins, epicatechins, and gallic acid, convey antioxidant and anti-inflammatory effects and may curb glaucomatous neurodegeneration.⁴⁹ In a glaucomatous mouse model, dietary supplementation with grape seed proanthocyanidins for 6 months reduced retinal inflammation, regulated oxidative stress, and enhanced RGC survival.⁴¹

There is an interesting emerging relationship between vitamin D insufficiency and glaucoma, which may potentially be mediated through anti-inflammatory mechanisms. Observational evidence suggests that lower vitamin D levels may be associated with the presence and severity of POAG across Asian, Caucasian, and African ethnicities, but not pseudoexfoliation glaucoma.^50–55 A French study found reduced ganglion cell complex (GCC) thickness in older participants with vitamin D deficiency without glaucoma or age-related macular degeneration compared to control (72.1 ± 7.4 μm vs 77.5 ± 7.5 μm; p = 0.028), suggesting a potential early manifestation of optic nerve dysfunction.⁵⁶

Several mechanisms have been postulated. Vitamin D regulates anti-inflammatory and immunomodulatory ocular and neurological cellular processes,^57–59 potentially conveying neuroprotective properties. While vitamin D supplementation has been shown to lower IOP in primate experiments,⁶⁰ evidence for this in humans is limited and conflicting.^51,53 High-quality randomized trials are needed to evaluate the efficacy of vitamin D supplementation in glaucoma neuroprotection.

Functional deficits

Compounding the primary insults of elevated IOP and vascular compromise are deficiencies in protective macular pigments and impairment in axonal function, both of which exacerbate visual decline in patients with glaucoma.

Macular pigment deficiency

While traditionally associated with age-related macular degeneration, macular pigment deficiencies are increasingly implicated in visual dysfunction in glaucoma. Lower macular pigment optical density (MPOD)—a measure of macular lutein, zeaxanthin, and meso-zeaxanthin—is associated with the presence and severity of foveal GCC loss.

The Macular Pigment and Glaucoma Trial demonstrated that glaucomatous eyes with foveal GCC involvement (n = 52) exhibit markedly lower MPOD at 0.25°, 0.5°, and 1° of retinal eccentricity compared to those without foveal GCC involvement (n = 36, p < 0.001 for all comparisons).⁶¹ This is in keeping with broader systematic review evidence linking MPOD depletion to foveal GCC loss and corresponding central 10-degree visual field defects, possibly through antioxidant-mediated pathways.⁶²

Supplementing with these macular carotenoids can help replenish macular pigment levels. This significantly increases MPOD volume and helps enhance visual performance (mesopic contrast sensitivity under glare conditions, for example) in individuals with glaucoma, with the greatest relative benefit observed in those with the lowest baseline macular pigment levels. Given these findings, the potential role of macular pigment augmentation in supporting macular health in glaucoma warrants further long-term investigation.^62,63

Impaired axonal function

Finally, disrupted visual pathway axonal conduction contributes to progressive vision loss, which may be stabilized or potentially even reversible on supplementation with citicoline and methylcobalamin.

Citicoline, an endogenous mononucleotide and cell-membrane precursor crucial for neuronal functionality, stability, and repair, is increasingly recognized for its multifarious neuroprotective benefits.⁶⁴ Supplementation with oral (1600 mg per day) or intramuscular (1000 mg per day) citicoline in glaucoma patients is associated with pattern electroretinogram and visual evoked potential improvements after 120 days.⁶⁵ Notably, citicoline supplementation may also improve quality of life,⁶⁶ and extended citicoline treatment for up to 8 years demonstrated further stabilization or even improvement of glaucomatous visual dysfunction.⁶⁵

Methylcobalamin is pivotal in myelin preservation, neuronal membrane stability, neurotransmitter synthesis, and overall axonal health. A prospective study found that daily supplementation with 1500 µg methylcobalamin over 4 years in patients with NTG reduced the progression of visual field loss. Indeed, only 14% of NTG patients (2 of 14 eyes) receiving methylcobalamin showed visual field deterioration, compared to 59% in the untreated control group (13 of 22 eyes; p = 0.008), a finding which was echoed on Cox proportional hazards modeling.⁶⁷ These findings reinforce the need to address axonal health as part of a holistic neuroprotective strategy when treating glaucoma.

Conclusion

The persistence of progressive vision loss despite adequate IOP control highlights the need for neuroprotective strategies that extend beyond pressure reduction. In this review, we introduced the NP-10 System as a framework to systematically address ten interrelated mechanisms that contribute to retinal ganglion cell vulnerability. An emerging body of evidence indicates that specific nutraceuticals may beneficially influence several of these mechanisms—spanning pressure-related, vascular, cellular, and functional domains—thereby complementing conventional therapy through a multitargeted, evidence-informed approach.

Current studies, while encouraging, are limited by modest sample sizes, heterogeneous methodologies, and variable follow-up durations. Moreover, inconsistency in formulation quality and bioavailability across nutraceutical products can complicate comparison and translation into practice. These challenges underscore the importance of rigorous, large-scale, long-term clinical trials to clarify efficacy, refine formulations, and ensure safety.

Against this backdrop, the NP-10 System offers a structured roadmap for advancing neuroprotective research and guiding clinicians who wish to integrate targeted nutritional support into comprehensive glaucoma management. By framing diverse evidence within a unified, mechanistic model, NP-10 helps transform a fragmented field into a coherent, actionable strategy for the future of glaucoma care.

Footnotes

None.

Declarations

ORCID iDs

Zhengyang Liu

Ghee Soon Ang

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