title: Trimethyltin initially activates the caspase 8/caspase 3 pathway for damaging the primary cultured cortical neurons derived from embryonic mice.
abstract: The organotin trimethyltin (TMT) is well known to cause neuronal damage in the central nervous system. To elucidate the mechanisms underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the neocortex of mouse embryos. A continuous exposure to TMT produced a decrease in cell viability as well as an increase in the number of cells with nuclear condensation/shrinkage at the exposure time window up to 24 hr. In addition to the events at the early time window, lactate dehydrogenase released was significantly elevated at the later exposure time from 36 to 48 hr. With a 3-hr exposure to TMT, a significant increase was observed in the activity of caspase 8, but not in that of caspase 9. TMT exposure produced no elevation in the level of cytochrome c released from mitochondria until 12 hr of exposure, with a significant facilitation of cytochrome c release at the exposure times of 16 and 24 hr. After the activation of caspase 8 by TMT exposure, caspase 3 activation and nuclear translocation of caspase-activated DNase were caused by exposure for 6 hr or longer. However, nuclear DNase II was elevated at the later time window of exposure. A caspase inhibitor completely prevented TMT from damaging the cells in any time window. Taken together, our data are the first demonstration that TMT toxicity is initially caused by activation of the caspase 8/caspase 3 pathway for nuclear translocation of DNases in cortical neurons in primary culture.
authors.affiliation: Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Hirakata, Osaka, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kuramoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Seko
authors.forename: Chie
authors.initials: C
authors.lastname: Sugiyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Shuto
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Ogita
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D015151:Immunoblotting; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D021381:Protein Transport; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D014298:Trimethyltin Compounds; C046488:trimethyltin; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D053148:Caspase 3; D053181:Caspase 8