Departments of Veterinary Anatomy and Veterinary Toxicology, College of Veterinary Medicine and Animal Medical Institute, Chonnam National University, Gwangju, Republic of Korea.
PLoS One. 2013 Aug 5;8(8):e70356. doi: 10.1371/journal.pone.0070356. Print 2013.
Trimethyltin (TMT) is an organotin compound with potent neurotoxic effects characterized by neuronal destruction in selective regions, including the hippocampus. Glycogen synthase kinase-3 (GSK-3) regulates many cellular processes, and is implicated in several neurodegenerative disorders. In this study, we evaluated the therapeutic effect of lithium, a selective GSK-3 inhibitor, on the hippocampus of adult C57BL/6 mice with TMT treatment (2.6 mg/kg, intraperitoneal [i.p.]) and on cultured hippocampal neurons (12 days in vitro) with TMT treatment (5 µM). Lithium (50 mg/kg, i.p., 0 and 24 h after TMT injection) significantly attenuated TMT-induced hippocampal cell degeneration, seizure, and memory deficits in mice. In cultured hippocampal neurons, lithium treatment (0-10 mM; 1 h before TMT application) significantly reduced TMT-induced cytotoxicity in a dose-dependent manner. Additionally, the dynamic changes in GSK-3/β-catenin signaling were observed in the mouse hippocampus and cultured hippocampal neurons after TMT treatment with or without lithium. Therefore, lithium inhibited the detrimental effects of TMT on the hippocampal neurons in vivo and in vitro, suggesting involvement of the GSK-3/β-catenin signaling pathway in TMT-induced hippocampal cell degeneration and dysfunction.
三甲基锡（TMT）是一种具有强烈神经毒性的有机锡化合物，其特征是在包括海马体在内的特定区域神经元破坏。糖原合酶激酶-3（GSK-3）调节许多细胞过程，并与几种神经退行性疾病有关。在这项研究中，我们评估了锂（一种选择性 GSK-3 抑制剂）对 TMT 处理（2.6mg/kg，腹腔内 [i.p.]）的成年 C57BL/6 小鼠海马体和 TMT 处理（5µM，体外培养 12 天）的培养海马神经元的治疗效果。锂（50mg/kg，i.p.，在 TMT 注射后 0 和 24 小时）显著减轻 TMT 诱导的小鼠海马体细胞退化、癫痫发作和记忆缺陷。在体外培养的海马神经元中，锂处理（0-10mM；在 TMT 应用前 1 小时）以剂量依赖性方式显著降低 TMT 诱导的细胞毒性。此外，在 TMT 处理或不处理的情况下，观察到小鼠海马体和培养海马神经元中 GSK-3/β-连环蛋白信号的动态变化。因此，锂抑制了 TMT 对体内和体外海马神经元的有害影响，表明 GSK-3/β-连环蛋白信号通路参与了 TMT 诱导的海马体细胞退化和功能障碍。
