In vivo depletion of endogenous glutathione facilitates trimethyltin-induced neuronal damage in the dentate gyrus of mice by enhancing oxidative stress.
Acute treatment with trimethyltin chloride (TMT) produces neuronal damage in the hippocampal dentate gyrus of mice. We investigated the in vivo role of glutathione in mechanisms associated with TMT-induced neural cell damage in the hippocampus by examining mice depleted of endogenous glutathione by prior treatment with 2-cyclohexen-1-one (CHO). In the hippocampus of animals treated with CHO 1h beforehand, a significant increase was seen in the number of single-stranded DNA-positive cells in the dentate gyrus when determined on day 2 after the injection of TMT at a dose of 2.0 mg/kg. Immunoblot analysis revealed that CHO treatment induced a significant increase in the phosphorylation of c-Jun N-terminal kinase in the cytosolic and nuclear fractions obtained from the dentate gyrus at 16 h after the TMT injection. There was also a concomitant increase in the level of phospho-c-Jun in the cytosol at 16 h after the injection. Expectedly, lipid peroxidation was increased by TMT in the hippocampus, and was enhanced by the CHO treatment. Moreover, CHO treatment facilitated behavioral changes induced by TMT. Taken together, our data indicate that TMT-induced neuronal damage is caused by activation of cell death signals induced at least in part by oxidative stress. We conclude that endogenous glutathione protectively regulates neuronal damage induced by TMT by attenuating oxidative stress.
Yoneyama
Masanori
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Nishiyama
Norito
N
Shuto
Makoto
M
Sugiyama
Chie
C
Kawada
Koichi
K
Seko
Keiichi
K
Nagashima
Reiko
R
Ogita
Kiyokazu
K
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003512:Cyclohexanones / Q000633:toxicity; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology* / Q000523:psychology; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology; D014298:Trimethyltin Compounds / Q000633:toxicity*
D003512:Cyclohexanones; D009419:Nerve Tissue Proteins; D014298:Trimethyltin Compounds; C046488:trimethyltin; C028215:2-cyclohexen-1-one; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione