Activation of c-Jun N-terminal kinase cascades is involved in part of the neuronal degeneration induced by trimethyltin in cortical neurons of mice.
The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the central nervous system. A systemic injection of TMT produced neuronal damage in the cerebral frontal cortex of mice. To elucidate the mechanism(s) underlying the toxicity of TMT toward neurons, we prepared primary cultures of neurons from the cerebral cortex of mouse embryos for use in this study. Microscopic observations revealed that a continuous exposure to TMT produced neuronal damage with nuclear condensation in an incubation time-dependent manner up to 48 h. The neuronal damage induced by TMT was not blocked by N-methyl-D-aspartate receptor channel-blocker MK-801. The exposure to TMT produced an elevation of the phosphorylation level of c-Jun N-terminal kinase (JNK)(p46), but not JNK(p54), prior to neuronal death. Under the same conditions, a significant elevation was seen in the phosphorylation level of stress-activated protein kinase 1, which activates JNKs. Furthermore, TMT enhanced the expression and phosphorylation of c-Jun during a continuous exposure. The JNK inhibitor SP600125 was effective in significantly but only partially attenuating the TMT-induced nuclear condensation and accumulation of lactate dehydrogenase in the culture medium. Taken together, our data suggest that the neuronal damage induced by TMT was independent of excitotoxicity but that at least some of it was dependent on the JNK cascades in primary cultures of cortical neurons.
Shuto
Makoto
M
Department of Medical Pharmacy, Setsunan University Faculty of Pharmaceutical Sciences, Osaka, Japan.
Seko
Keiichi
K
Kuramoto
Nobuyuki
N
Sugiyama
Chie
C
Kawada
Koichi
K
Yoneyama
Masanori
M
Nagashima
Reiko
R
Ogita
Kiyokazu
K
D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity; D015151:Immunoblotting; D007274:Injections, Intraperitoneal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013997:Time Factors; D014298:Trimethyltin Compounds / Q000008:administration & dosage / Q000633:toxicity*
D000873:Anthracenes; D005659:Fungicides, Industrial; D014298:Trimethyltin Compounds; C046488:trimethyltin; C432165:pyrazolanthrone; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4