NAD+ administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia

Abstract

Nicotinamide adenine dinuleotide (NAD+) plays critical roles in multiple biological functions. Previous studies have indicated that NAD+ treatment decreases oxidative stress-induced death of primary neurons and astrocytes. Intranasal administration of NAD+ also reduces brain damage in a rat model of transient focal brain ischemia. However, the mechanisms underlying this protective effect remain unknown. In this study, we used a mouse model of brain ischemia to test our hypothesis that NAD+ decreases ischemic brain damage partially by preventing autophagy. Adult male mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min, and NAD+ was administered intraperitoneally (i.p.) immediately after reperfusion started. We found that administration with 50mg/kg NAD+ led to significant decreases in infarct size, edema formation, and neurological deficits at 48h after ischemia. NAD+ administration also significantly decreased brain ischemia-induced autophagy in the cortex and hippocampus. We further found that prevention of autophagy by 3-methyladenine (3-MA), a selective autophagy inhibitor, significantly reduced ischemic brain damage, suggesting an important role of autophagy in the ischemic brain injury in our animal model. Collectively, our findings have suggested that NAD+ administration decreases ischemic brain damage at least partially by blocking autophagy. This is the first suggested mechanism regarding the protective effects of NAD+ in cerebral ischemia, which further highlights the promise of NAD+ for treating brain ischemia.