title: Trimethyltin-induced apoptosis is associated with upregulation of inducible nitric oxide synthase and Bax in a hippocampal cell line.
abstract: Trimethyltin (TMT) produces selective neuronal degeneration in the central nervous system (CNS), in which the hippocampus is the most sensitive area. Since previous studies have been conducted in either non-neural cells or mixed primary cultures, an immortalized hippocampal neuronal cell line (HT-22 cell) was used to assess the mechanism and mode of death produced by TMT. The compound produced a time- and concentration-dependent apoptotic death that was caspase-mediated. Excessive generation of reactive oxygen species (ROS) and subsequent reduction of mitochondrial membrane potential (DeltaPsim) were involved in the cytotoxicity. Scavenging of ROS by a free radical trapping agent or inhibition of the mitochondrial permeability transition (MPT) pore significantly reduced cell death. Additionally, TMT increased expression of inducible nitric oxide synthase (iNOS) by activation of the redox-sensitive transcription factor NFkappaB. Pharmacologic inhibition studies showed that the iNOS-mediated NO generation increased expression of Bax and then mitochondrial-mediated apoptosis. It was concluded that excessive ROS generation initiated the apoptotic cell death by upregulating iNOS followed by increased Bax expression which then led to loss of DeltaPsim and caspase-executed cell death. This study is the first to report in a neuronal cell model that TMT stimulates induction of iNOS, which then increases cellular levels of reactive nitrogen species (RNS) to initiate apoptotic death.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Prabhakaran
authors.forename: J L
authors.initials: JL
authors.lastname: Borowitz
authors.forename: G E
authors.initials: GE
authors.lastname: Isom
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C494828:Bax protein, rat; D061945:Caspase Inhibitors; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009589:Nitrogen Oxides; D016376:Oligonucleotides, Antisense; D010455:Peptides; D017382:Reactive Oxygen Species; C118258:SN50 peptide; D014298:Trimethyltin Compounds; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C015388:nitrones; C046488:trimethyltin; D009569:Nitric Oxide; C029217:phenyl-N-tert-butylnitrone; D016572:Cyclosporine; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D019331:NG-Nitroarginine Methyl Ester