Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function.
The purpose of the current study was to investigate aspects of improved bioenergetic function using nicotinamide during stroke. Using a global ischemia-reperfusion mouse model, ATP was depleted by 50% in the brain. The use of nicotinamide to provide a large reserve of brain NAD+ restored ATP levels to 61% of control levels. Alternatively, using nicotinamide as a PARP inhibitor restored ATP levels up to 72%. However, using a large reserve of NAD+ in the brain together with PARP inhibition proved to be additive, restoring ATP to 85% of control levels during the first critical 5 min of reperfusion. NAD+ and ATP levels correlated almost exactly. Brain mitochondrial function was also examined after cerebral ischemia-reperfusion. State 3 respiration of complex I was found to be abolished. However, this was a non-permanent inhibition of activity in vitro, since (NADH ubiquinone oxideroductase) complex I activity in these mitochondria was restored upon the addition of NADH. In vivo, the use of increased brain NAD+ and PARP inhibition was able to partially restore mitochondrial respiration. Taken together, the results show that nicotinamide offers a substantial protective role in terms of preservation of cellular ATP and mitochondrial NAD-linked respiration.
D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009536:Niacinamide / Q000378:metabolism / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015424:Reperfusion; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D009536:Niacinamide; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases