Vitamin B and choline supplementation found neuroprotective in glaucoma models

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Swedish researchers, led by senior author James R. Tribble, BSc, PhD, reported that oral B₆, B₉, B₁₂, and choline were neuroprotective against glaucoma in two animal models. The investigators are from the Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden. They reported their results in Cell Reports Medicine.

There currently are no neuroprotective therapies available to treat glaucoma, and discovery is complicated by the disease's complexity, the investigators commented.

“Recent work has identified metabolic dysfunction in the retina and optic nerve occurring prior to detectable neurodegeneration of retinal ganglion cells (RGCs) in glaucoma (via transcriptomic and metabolomic analyses), presenting the potential for neuroprotection prior to the initiation of neurodegenerative cascades. Loss of mitochondrial function and transport in RGCs,^2,3 reduced energy capacity,⁴ loss of the ability to maintain nicotinamide adenine dinucleotide,^5,6 and the depletion of alternative energy sources^7,8 have all been identified early in glaucoma in human patients and animal models,” they explained.

The authors cited studies in which elevated levels of homocysteine were associated with major diseases such as cardiovascular disease, diabetes, and Alzheimer’s disease, although this is typically in the form of hyperhomocysteinemia, where homocysteine is elevated in the blood.⁹ In addition, small human studies have suggested that homocysteine may be elevated in the blood and aqueous humor of certain glaucomas.¹⁰ Mouse models of hyperhomocysteinemia present significant retinal degenerative phenotypes, including vascular compromise and RGC degeneration.^11-13 Supporting this, intravitreal injection of homocysteine in high concentrations can induce RGC death.^14,15

Based on those studies, Tribble and colleagues hypothesized that elevated homocysteine directly compounds RGC death in glaucoma and is related to dysfunction in one-carbon metabolism.

To determine this, they used mouse and rat models of ocular hypertension and retrospectively evaluated human epidemiologic data to investigate the effect of homocysteine and one-carbon metabolism, a pathway that transfers one-carbon units to molecules, and their impact on neurodegeneration.

Main study findings

“Our study demonstrated that elevated homocysteine worsens glaucoma outcome in animal models but this effect is mild. In humans, elevation of serum homocysteine has no detectable effect on glaucoma-related outcomes or disease progression. Early elevation of homocysteine in the retina is a marker of dysfunctional one-carbon metabolism, which we identify as an early and sustained feature of glaucoma. This is associated with dysfunctional regulation of genes and proteins that interact with key one-carbon metabolism cofactors and precursors: vitamin B₆, B₉, B₁₂, and choline,” they reported.

Importantly, this supplementation of vitamin B₆, B₉, B₁₂, and choline provided neuroprotection against the death of RGCs in acute and mild and chronic animal models of glaucoma, including protection of visual function. This was independent of the intraocular pressure.

Tribble and colleagues believe these findings ultimately can be useful in treatment of humans with glaucoma.

References

1. Tribble JR, Wong VHY, Stuart KV, et al. Dysfunctional one-carbon metabolism identifies vitamins B₆, B₉, B₁₂, and choline as neuroprotective in glaucoma. Cell Rep Med. 2025;6:102127. Published online May 20. https://doi.org/10.1016/j.xcrm.2025.102127.

2. Tribble JR, Vasalauskaite A, Redmond T, et al. Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma. Brain Commun. 2019;1:fcz035.

3. Quintero H, Shiga Y, Belforte N, et al. Restoration of mitochondria axonal transport by adaptor Disc1 supplementation prevents neurodegeneration and rescues visual function. Cell Rep. 2022;40:111324.

4. Belforte N, Agostinone J , Alarcon-Martinez L, et al. AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma. Mol Neurodegener. 2021;16:43.

5. Williams PA, Harder JM, Foxworth NE, et al. Vitamin B-3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017;355:756-760.

6. Tribble JR, Otmani A, Sun S, et al. Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction. Redox Biol. 2021;43:101988.

7. Harder JM, Guymer C, Wood JPM, et al. Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin. Proc Natl Acad Sci USA. 2020;117:33619-33627.

8. Harun-Or-Rashid M, Pappenhagen N, Zubricky R, et al.MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two models of glaucoma.Neurobiol Dis. 2020;141:104944.

9. McCaddon A, Miller JW.Homocysteine-a retrospective and prospective appraisal. Front Nutr. 2023;10:1179807.

10. Xu F, Zhao X, Zeng SM, Li L, Zhong HB, Li M. Homocysteine, B vitamins, methylenetetrahydrofolate reductase gene, and risk of primary open-angle glaucoma: a meta-analysis. Ophthalmology. 2012;119:2493-2499.

11. Ganapathy PS, Moister B, Roon P, et al. Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-beta-synthase mutant mouse. Invest Ophthalmol Vis Sci. 2009;50:4460-4470.

12. Tawfik A, Al-Shabrawey M, Roon P, et al. Alterations of retinal vasculature in cystathionine-Beta-synthase mutant mice, a model of hyperhomocysteinemia. Invest Ophthalmol Vis Sci. 2013;54:939-949.

13. Yu M, Sturgill-Short G, Ganapathy P, et al.Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia. Exp Eye Res. 2012;96:124-131.

14. Moore P, El-sherbeny A, Roon P, et al. Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine.Exp Eye Res. 2001;73:45-57.

15. Chang HH, Lin DPC, Chen YS, et al. Intravitreal homocysteine-thiolactone injection leads to the degeneration of multiple retinal cells, including photoreceptors. Mol Vis. 2011;17:1946-1956.