Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia

Excessive poly( ADP-ribose) polymerase-1 ( PARP-1) activation plays a significant role in ischemic brain damage. Increasing evidence has supported the hypothesis that PARP-1 induces cell death by depleting intracellular NAD(+). Based on our in vitro finding that NAD(+) treatment can abolish PARP-1-mediated cell death, we hypothesized that NAD(+) administration may decrease ischemic brain injury. In this study, we used a rat model of transient focal ischemia to test this hypothesis. We observed that intranasal NAD(+) delivery significantly increased NAD(+) contents in the brains. Intranasal delivery with 10 mg/kg NAD(+) at 2 hours after ischemic onset profoundly decreased infarct formation when assessed either at 24 or 72 hours after ischemia. The NAD(+) administration also significantly attenuated ischemia-induced neurological deficits. In contrast, intranasal administration with 10 mg/kg nicotinamide did not decrease ischemic brain damage. These results provide the first in vivo evidence that NAD(+) metabolism is a new target for treating brain ischemia, and that NAD(+) administration may be a novel strategy for decreasing brain damage in cerebral ischemia and possibly other PARP-1-associated neurological diseases.