Involvement of independent mechanism upon poly(ADP-ribose) polymerase (PARP) activation in methylmercury cytotoxicity in rat cerebellar granule cell culture.

Abstract

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.

• Authors: Motoharu Sakaue, Naoko Mori, Maiko Okazaki, Mayuka Ishii, Yayoi Inagaki, Yuka Iino, Kiyomi Miyahara, Mai Yamamoto, Takeshi Kumagai, Shuntaro Hara, Masako Yamamoto, Kazuyoshi Arishima
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 86 Issue 15 Pg. 3427-34 (Nov 15 2008) ISSN: 1097-4547 [Electronic] United States
• PMID: 18627028 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Free Radicals
• Isoquinolines
• Methylmercury Compounds
• Piperidines
• 3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone
• Poly(ADP-ribose) Polymerases
• Glutathione

Topics

• Animals
• Cell Death (physiology)
• Cells, Cultured
• Cerebellum (drug effects, metabolism)
• Enzyme Activation (physiology)
• Enzyme Inhibitors (pharmacology)
• Free Radicals (metabolism)
• Glutathione (drug effects, metabolism)
• Humans
• Isoquinolines (pharmacology)
• Methylmercury Compounds (toxicity)
• Microscopy, Fluorescence
• Neurons (drug effects, metabolism)
• Piperidines (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats