Short-term high-dose nicotinamide treatment across glaucoma subtypes reveals increased mtDNA content and minimal metabolomic change in blood

In glaucoma, retinal ganglion cell degeneration has been linked to declining mitochondrial metabolic capacity. Nicotinamide (NAM) supplementation has emerged as a potential treatment for this. We assessed the effects of a 2-week NAM supplementation on blood buffy coat mitochondrial content (qPCR to assess mtDNA amount per cell) and the plasma metabolome (small-molecular-weight high-resolution mass spectrometry) in 90 glaucoma subjects from 3 different glaucoma subtypes (high tension glaucoma (HTG), normal tension glaucoma (NTG), and pseudoexfoliative glaucoma (PEXG), n = 30 per group), and 30 healthy controls with similar age and sex distribution. At baseline (pre-NAM), only ethylmalonic acid, a compound related to defects in β-oxidation and mitochondrial dysfunction, was found to be modestly increased in the 3 glaucoma subtypes in comparison to controls. All groups showed a similar metabolome response to treatment with a specific increase in NAM and related species (1-methylnicotinamide, 6-hydroxynicotinamide, N1-methyl-2-pyridone-5-carboxamide), increased 5-methylcytosine, and decreased 4-pyridoxic acid. Between groups, only sarcosine had a different response, with a small reduction in HTG and NTG post-treatment. NAM treatment resulted in a significant but slight within-group increase in blood mtDNA amount in controls and HTG (12 % and 17 %, respectively). This study suggests that NAM treatment leads to similar plasma metabolome changes between glaucoma groups and controls, which predominantly reflect increased NAM metabolites and intermediates, with minimal effects on the wider metabolome, and a modest increase in mtDNA amount in HTG and controls. As this was observed in a short-term accelerated dosing context, long-term and larger studies with additional timepoints and greater adjustment for systemic metabolic factors will be required to provide more information on the long-term effects of oral NAM supplementation.