Oxidative stress and PARP activation mediate the NADH-induced decrease in glioma cell survival.

Reduced nicotinamide adenine dinucleotide (NADH) plays key roles in energy metabolism and mitochondrial functions. However, there has been little information regarding the effect of NADH on cell survival. In this study we determined the effect of NADH treatment on the survival of glioma cells. We found that treatment of C6 glioma cells with as low as 1 μM NADH for 24 hrs significantly decreased the survival of these cells, and that treatment of the cells with 1000 μM NADH for 4 days decreased the survival of the cells by nearly 90%. This effect of NADH on glioma cells appears to be mediated by oxidative stress, as indicated by our findings that NADH treatment induced an increase in intracellular reactive oxygen species, and that two antioxidants, N-acetyl cysteine and Trolox, significantly attenuated the effect of NADH. We also found that NADH treatment induced an increase in poly(ADP-ribose) polymerase (PARP) activity, and that PARP inhibitors decreased the effect of NADH on the survival of glioma cells. These observations suggest that NADH reduces the cell survival at least partially by activating PARP. Collectively, our studies demonstrated a novel biological property of NADH - NADH decreases glioma cell survival by increasing oxidative stress and PARP activation. These results also suggest that NADH may have therapeutic potential for treating gliomas.