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Author(s): Ali Poyan Mehr [sup.1] , Mei T. Tran [sup.1] , Kenneth M. Ralto [sup.1] [sup.2] [sup.3] , David E. Leaf [sup.4] , Vaughan Washco [sup.1] , Joseph Messmer [sup.1] [...], Nicotinamide adenine dinucleotide (NAD.sup.+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD.sup.+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD.sup.+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD.sup.+ fell, quinolinate rose, and QPRT declined. QPRT.sup.+/- mice exhibited higher quinolinate, lower NAD.sup.+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD.sup.+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD.sup.+ biosynthesis may be a feature of high-risk hospitalizations for which NAD.sup.+ augmentation could be beneficial. Impaired NAD.sup.+ biosynthesis may be a common feature of high-risk hospitalizations for which NAD.sup.+ augmentation could improve therapeutic outcome.

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. [ABSTRACT FROM AUTHOR]