Role of NAD+ and FAD in Ischemic Stroke Pathophysiology: An Epigenetic Nexus and Expanding Therapeutic Repertoire.

The redox coenzymes viz., oxidized β-nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD) by way of generation of optimal reducing power and cellular energy currency (ATP), control a staggering array of metabolic reactions. The prominent cellular contenders for NAD+ utilization, inter alia, are sirtuins (SIRTs) and poly(ADP-ribose) polymerase (PARP-1), which have been significantly implicated in ischemic stroke (IS) pathogenesis. NAD+ and FAD are also two crucial epigenetic enzyme-required metabolites mediating histone deacetylation and poly(ADP-ribosyl)ation through SIRTs and PARP-1 respectively, and demethylation through FAD-mediated lysine specific demethylase activity. These enzymes and post-translational modifications impinge on the components of neurovascular unit, primarily neurons, and elicit diverse functional upshots in an ischemic brain. These could be circumstantially linked with attendant cognitive deficits and behavioral outcomes in post-stroke epoch. Parsing out the contribution of NAD+/FAD-synthesizing and utilizing enzymes towards epigenetic remodeling in IS setting, together with their cognitive and behavioral associations, combined with possible therapeutic implications will form the crux of this review.