NAD <sup> <b>+</b> </sup> precursor nutritional supplements sensitize the brain to future ischemic events
Wensheng Qu, Kenneth M. Ralto, Tao Qin, Yinhong Cheng, Weifeng Zong, Xiang Luo, Miguel A. Pérez‐Pinzón, Samir M. Parikh, Cenk Ayata
Abstract
Nicotinamide adenine dinucleotide (NAD + ) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD + precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD + precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD + precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD + precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset.