Poly(ADP-ribose) polymerase (PARP) activation plays a role in repairing injured
DNA, while its overactivation is involved in various diseases, including neuronal degradation. In the present study, we investigated the use of a
PARP inhibitor, 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), whether methylmercury-induced cell death in the primary culture of cerebellar granule cells involved PARP activation. DPQ decreased the methylmercury-induced cell death in a dose-dependent manner. Unexpectedly, this protective effect was DPQ specific; none of the other PARP inhibitors--1,5-dihydroxyisoquinoline,
3-aminobenzamide, or PJ34--affected neuronal cell death. Methylmercury-induced cell death involves the decrease of
glutathione (GSH) and production of
reactive oxygen species. Therefore, to understand the mechanism by which DPQ inhibits cytotoxicity, we first studied the effect of DPQ on
buthionine sulfoximine- or
diethyl maleate-induced death of primary cultured cells and human
neuroblastoma IMR-32 cells, both of which are mediated by GSH depletion. DPQ inhibited the cell death of both cultured cells, but it did not restore the decrease of cellular GSH by
buthionine sulfoximine to the control level. Second, we evaluated the
antioxidant activity of
PARP inhibitors by methods with
ABTS (2-2'-azinobis(3-ethylbenzothiazoline 6-sulfonate) or DPPH (1,1-
diphenyl-2-picrylhydrazyl) used as a radical because
antioxidants also efficiently suppress methylmercury-induced cell death. The
antioxidant activity of DPQ was the lowest among the tested
PARP inhibitors. Taken together, our results indicate that DPQ effectively protects cells against methylmercury- and GSH depletion-induced death. Furthermore, they suggest that DPQ exerts its protective effect through a mechanism other than PARP inhibition and direct antioxidation, and that PARP activation is not involved in methylmercury-induced neuronal cell death.