Activation of c-Jun N-Terminal Kinase Cascades Is Involved in Part of the Neuronal Degeneration Induced by Trimethyltin in Cortical Neurons of Mice

Makoto Shuto; Keiichi Seko; Nobuyuki Kuramoto; Chie Sugiyama; Koichi Kawada; Masanori Yoneyama; Reiko Nagashima; Kiyokazu Ogita

doi:10.1254/jphs.08211FP

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Activation of c-Jun N-Terminal Kinase Cascades Is Involved in Part of the Neuronal Degeneration Induced by Trimethyltin in Cortical Neurons of Mice

Makoto Shuto, Keiichi Seko, Nobuyuki Kuramoto, Chie Sugiyama, Koichi Kawada, Masanori Yoneyama, Reiko Nagashima, Kiyokazu Ogita

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Makoto Shuto
Department of Medical Pharmacy, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Laboratory of Molecular Pharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Japan
Keiichi Seko
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Nobuyuki Kuramoto
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Chie Sugiyama
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Koichi Kawada
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Masanori Yoneyama
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Reiko Nagashima
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan
Kiyokazu Ogita
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan

Keywords: c-Jun N-terminal kinase, cortical neuron, neuronal death, stress-activated protein kinase 1, trimethyltin

JOURNAL FREE ACCESS

2009 Volume 109 Issue 1 Pages 60-70

DOI https://doi.org/10.1254/jphs.08211FP

View "Advance Publication" version (January 2, 2009).

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Abstract

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.

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