Indomethacin Ameliorates Trimethyltin-Induced Neuronal Damage in Vivo by Attenuating Oxidative Stress in the Dentate Gyrus of Mice

• Published in: Biological & Pharmaceutical Bulletin Vol. 34; no. 12; pp. 1856 - 1863
• Main Authors: Huong, Nguyen Quynh, Nakamura, Yukary, Kuramoto, Nobuyuki, Yoneyama, Masanori, Nagashima, Reiko, Shiba, Tatsuo, Yamaguchi, Taro, Hasebe, Shigeru, Ogita, Kiyokazu
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2011; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: 4-Hydroxynonenal; Aldehydes - metabolism; Animals; Calpain; Caspase 3 - metabolism; Caspase-3; cyclooxygenase; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Cyclooxygenase-1; Cyclooxygenase-2; Data processing; Degeneration; Dentate gyrus; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; DNA; Gene expression; Granule cells; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Indomethacin; Indomethacin - pharmacology; Indomethacin - therapeutic use; Lipid peroxidation; Male; Mice; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Microglial cells; Nerve Degeneration - chemically induced; Nerve Degeneration - drug therapy; Nerve Degeneration - metabolism; neuronal degeneration; Neurons; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Organotin; Oxidative stress; Oxidative Stress - drug effects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Trimethyltin; Trimethyltin Compounds - toxicity
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.34.1856

The organotin trimethyltin (TMT) is well known to cause neuronal degeneration in the hippocampal dentate gyrus of mice. The first purpose of the present study was to examine whether the cyclooxygenase (COX) inhibitor indomethacin could ameliorate neuronal degeneration in the dentate gyrus of mice following TMT treatment in vivo. The systemic injection into mice of TMT at 2.8 mg/kg produced activation of endogenous caspase-3 and calpain, enhanced the gene expression of COX-1 and COX-2, activated microglial cells, and caused the formation of the lipid peroxidation product 4-hydroxynonenal in the hippocampus. Given at 12-h post-TMT treatment, the systemic injection of indomethacin (5 or 10 mg/kg, subcutaneously) significantly decreased the TMT-induced damage to neurons having active caspase-3 and single-stranded DNA in the dentate granule cell layer of the hippocampus. The results of the α-Fodrin degradation test revealed that the post-treatment with indomethacin was effective in attenuating TMT-induced activation of endogenous caspases and calpain in the hippocampus. In TMT-treated animals, interestingly, the post-treatment with indomethacin produced not only activation of microglial cells in the dentate gyrus but also the formation of 4-hydroxynonenal in the dentate granule cell layer. Taken together, our data suggest that COX inhibition by indomethacin ameliorated TMT-induced neuronal degeneration in the dentate gyrus by attenuating intensive oxidative stress.