Poly(ADP-ribose) polymerase-1 consumes NAD to catalyze poly(ADP-ribosyl)ation of target proteins, which modulates various biological functions. However, excessive poly(ADP-ribose) polymerase-1 activation mediates oxidative cell death. Our recent studies have indicated that NAD can enter into astrocytes to prevent poly(ADP-ribose) polymerase-1 cytotoxicity. In this study, we show that NADH can also enter into astrocytes, which can significantly decrease poly(ADP-ribose) polymerase-1-induced astrocyte death even when applied 3-4 h after poly(ADP-ribose) polymerase-1 activation. The protective effects can be produced by 10 muM NADH, which is significantly lower than that required for NAD to be protective. These results provide novel information suggesting that NADH can be used for decreasing poly(ADP-ribose) polymerase-1 toxicity, and extracellular NADH can enter into astrocytes to influence cellular functions.