FIG. 5. Mechanism of NO-mediated neurotoxicity. DNA damaged by NO activates PARS, which depletes cells of NAD by poly-ADP-ribosylating nuclear proteins. Poly(ADP-ribose) is rapidly degraded by poly(ADP-ribose) glycohydrolase. This futile cycle continues during the prolonged PARS activation. It takes an equivalent of four ATPs to resynthesize NAD from nicotinamide (NAm) via nicotinamide mononucleotide (NMN), a reaction that requires phosphoribosyl pyrophosphate (PRPP) and ATP. The depletion of energy ultimately leads to cell death. (From ref. 71.)