Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Nzoughet, Judith Kouassi; Barca, Juan Manuel Chao de la; Guehlouz, Khadidja; Leruez, Stéphanie; Coulbault, Laurent; Allouche, Stéphane; Bocca, Cinzia; Muller, Jeanne; Amati‐Bonneau, Patrizia; Gohier, Philippe; Bonneau, Dominique; Simard, Gilles; Miléa, Dan; Lenaers, Guy; Procaccio, Vincent; Reynier, Pascal

doi:10.1101/571638

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…An additional key difference in metabolic profiles between control and glaucoma retinas was a decrease in retinal nicotinamide (NAM). NAM levels were lower in D2 retinas compared to controls consistent with decreased retinal NAD levels in this model (10) and decreased serum NAM levels in primary open angle glaucoma patients (18). We have previously demonstrated that NAM confers a robust neuroprotection against damaging IOP insults.…”

supporting

confidence: 73%

Oral pyruvate prevents glaucomatous neurodegeneration

Williams

Harder

Guymer

et al. 2020

Preprint

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Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that agerelated bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.

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supporting

confidence: 73%

Oral pyruvate prevents glaucomatous neurodegeneration

Williams

Harder

Guymer

et al. 2020

Preprint

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“…In glaucoma models, diets supplemented with niacin have been demonstrated to protect RGCs from degeneration by supporting mitochondrial health and metabolism (14)(15)(16). In this respect, vitamin B3 has been included in the panel of neuroprotective strategies in glaucoma patients in which low vitamin B3 levels have been demonstrated (17). Accordingly, vitamin B3 supplementation appears to counteract RGC dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

Melecchi,

Amato,

Dal Monte

et al. 2023

Front. Med.

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IntroductionMuch interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase.MethodsOcular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis.ResultsThe present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination.ConclusionNiacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.

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NAD precursors cycle between host tissues and the gut microbiome

Chellappa

McReynolds

et al. 2021

Preprint

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Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in both mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome. We find that preferred dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports gut microbiome NAD synthesis. In addition, the microbiome converts nicotinamide, originating from the host circulation, into nicotinic acid. Host tissues uptake and utilize this microbiome-derived nicotinic acid for NAD synthesis, maintaining circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

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Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Cited by 3 publications

References 22 publications

Oral pyruvate prevents glaucomatous neurodegeneration

Oral pyruvate prevents glaucomatous neurodegeneration

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

NAD precursors cycle between host tissues and the gut microbiome

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