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Editors Selection IGR 12-3

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Comment by Louis Pasquale on:

71509 Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice, Williams PA; Harder JM; Foxworth NE et al., Science, 2017; 355: 756-760

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New approaches to protect the optic nerve from glaucomatous degeneration are always welcome. Williams and coworkers perform a rigorous set of experiments in a mouse model of glaucoma (the DBA/2J mouse) characterized by variable-onset but age-related iris depigmentation, immune deviation, elevated intraocular pressure (IOP) and optic nerve degeneration. The RNA sequence expression in RGCs of DBA/2J mice at nine months, a time when there is elevated IOP but no optic nerve damage, demonstrates an increase in mitochondrial gene expression suggestive of a cellular stress response. In DBA/2J mice, but not in controls, these biochemical changes were accompanied by structural reductions in mitochondrial cristae surface area. Cristae are folds in the inner mitochondrial membranes that allow electron transport and ATP formation to occur. The conversion of NADH to NAD+ is a key upstream step in the generation of a hydrogen ion gradient that leads to ATP formation. The authors found that an early reduction of NAHD and NAD+ in RGCs represents an important biochemical signature of aging that was present in both DBA/2J mice and controls. The authors therefore hypothesized that reduction of cellular respiration served as a sensitizer to make RGCs vulnerable to glaucomatous degeneration. Mice were treated with 0.55g/kg/day nicotinamide (NAM), a precursor of NAD, in the drinking water at either six months or nine months of age and followed until one year of age. Approximately 50% of control eyes exhibited > 50% axon loss at 12 months, while ~22% of treated eyes exhibited such loss when NAM was started at nine months of age. When the NAM dose was increased to 2g/kg/day the optic nerve protection was even more pronounced. Furthermore. NAM restored the normal ultra-structural features of mitochondrial cristae. These neuro-protective effects were achieved without lowering IOP. Similar neuro-protective effects were seen when RGCs from DBA/2J mice over-expressed nicotinic acid mononucleotide adenyltransferase, an enzyme that generates NAD.

These experiments are certainly elegant, but there are a few issues to consider. The animals were sex-matched but the percentage of males and females was not provided. While this may seem like a minor point, the subsequent performance of RCTs requires such preclinical knowledge. Second, it would be interesting to carry out comparable experiments in the micro-bead glaucoma model. While there is probably immune involvement in human open angle glaucoma, the immune alterations in the DBA/2J model are likely more pronounced.

Their results support the therapeutic use of NAM in glaucoma; yet, they used NAM doses that are probably not feasible in humans

Finally the authors make a strong statement that their results support the therapeutic use of NAM in glaucoma; yet, they used NAM doses that are probably not feasible in humans. NAM, also known as niacin or vitamin B3, can produce cystoid macula edema at doses of three to six g/day, but this side-effect has been reported with lower doses.^1,2 Systemically niacin commonly produced facial cutaneous flushing, a side effect that could curtail its use. The lowest NAM dose that was associated with a statistically significant neuro-protective effect was not reported. Overall structural and functional tests suggest that these doses enhance retinal integrity but there is no mention of whether idiopathic retinal toxicity was noted in any of the mice that received NAM.

Overall, we hope that the authors find ways to translate their findings to glaucoma patients. It should be noted that while the favorable effect of NAM on serum lipid profile is unquestioned, it failed to have definitive effects on cardiovascular endpoints or all-cause mortality in a recent meta-analysis of 13 clinical studies.³ Perhaps, investigators can leverage pre-existing clinical and epidemiological data to test whether NAM intake favorably alters the course of glaucoma.

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