VITAMIN B3 TREATMENT FOR GLAUCOMA

 

• Increasing age and high intra-ocular pressure (IOP) interact to drive neurodegeneration.
• An experiment was conducted by a group of researchers using DBA/2J (D2) mice, a widely used model of chronic, age-related, inherited glaucoma to analyze the effect of vitamin B3.

https://pubmed.ncbi.nlm.nih.gov/28209901/

• RNA-sequencing (RNA-seq) was utilized to elucidate age and IOP-dependent molecular changes within retinal ganglion cells (RGCs) that precede glaucomatous neurodegeneration.
• Emerging evidence suggests that imbalances in the relative proportions of mitochondrial proteins encoded by nuclear and mitochondrial genomes negatively impact mitochondrial function.
• Differential expression of genes encoding mitochondrial proteins, and significant enrichment of differentially expressed (DE) genes in the mitochondrial dysfunction and oxidative phosphorylation pathways further point to mitochondrial abnormalities.
• Electron microscopy (EM) studies in the experiment revealed abnormal mitochondria with reduced cristae volume in the dendrites of D2 RGCs, but not in those of control RGCs.
• A number of studies demonstrate that mitochondrial perturbations are among the very first changes occurring within RGCs during glaucoma.
• Retinal levels of nicotinamide adenine dinucleotide (NAD+; a key molecule in energy and redox metabolism) decrease with age, and render aging neurons vulnerable to disease-related insults.
• The current study reported early decreases in metabolites that are central to healthy mitochondrial metabolism and protection from oxidative stress (NAD+ and NADH [total NAD; NAD(t)], GSH and GSSG [total glutathione; glutathione(t)]).
• RGCs go through a period of mitochondrial stress and metabolite depletion, potentially moving towards fatty acid metabolism. Fatty acid β-oxidation can increase generation of free radicals/reactive oxygen species (ROS).
• Oral supplementation of vitamin B3/nicotinamide (NAM; a precursor of NAD) has been successfully used to correct disturbances in NAD+ metabolism in two mouse models of pre-eclampsia.
• In this experiment NAM was administered to D2 mice, initially at the same dose (550 mg/kg/d, NAMLo). NAM administration in drinking water prevented the decline of NAD levels through to 12 months (a standard end stage for assessing neurodegeneration in this glaucoma model).
• Supporting the neuronal vulnerability hypothesis, NAMLo did not alter IOP, but protected from glaucoma. NAM was protective both prophylactically (starting at 6 months, prior to IOP elevation in most eyes) and interventionally (starting at 9 months, when the majority of eyes have had continuing IOP elevation).
• NAM significantly reduced the incidence of optic nerve degeneration, prevented RGC soma loss and retinal nerve fiber layer thinning, and protected visual function as assessed by PERG.
• NAM administration was sufficient to inhibit the formation of dysfunctional mitochondria with abnormal cristae and also limited synapse loss that occurs in this model.
• Attempting to further decrease the probability of glaucoma, a higher dose of NAM was administered (2000mg/kg/d; NAMHi). NAMHi was extremely protective with 93% of treated eyes having no optic nerve damage. The degree of protection afforded by administering this single molecule is unprecedented and unanticipated.
• Although NAMLo demonstrates a clear neuroprotective effect (no effect on IOP), NAMHi lessens the degree of IOP elevation.
• This indicates that NAM can protect against age-related pathogenic processes in additional cell types to RGCs. Therefore vitamin B3/NAM, a single molecule that protects against both IOP elevation and neural vulnerability, has great potential for glaucoma treatment, however human studies are needed.