title: Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells.
abstract: In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 microM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H(2)O(2) are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative species generation, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 microM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.
authors.affiliation: Neurotoxicology Laboratory, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-1333, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gunasekar
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Prabhakaran
authors.forename: V
authors.initials: V
authors.lastname: Eybl
authors.forename: J L
authors.initials: JL
authors.lastname: Borowitz
authors.forename: G E
authors.initials: GE
authors.lastname: Isom
mesh_terms: D000470:Alkaloids; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053119:Benzophenanthridines; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009573:Nitrites; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate; D017392:Thiobarbituric Acid Reactive Substances; D014298:Trimethyltin Compounds; C046488:trimethyltin; D016291:Dizocilpine Maleate; C016299:chelerythrine; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D019331:NG-Nitroarginine Methyl Ester