Dawson R, Patterson T A, Eppler B
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Neurochem Res. 1995 Jul;20(7):847-58. doi: 10.1007/BF00969697.
Trimethyltin (TMT) is a toxic alkyltin compound that is known to produce neuronal necrosis in the CNS. The present study examined the effects of TMT on the release of excitatory amino acids (EAA) from cortical slices prepared from adult and aged (24 months old) rats. The calcium dependence of TMT-induced EAA efflux was evaluated and compared to other neurotoxic agents. The actions of TMT were also evaluated in an astrocyte culture model to assess glial contributions to TMT-induced EAA efflux. TMT (10-1000 microM) evoked a dose-related increase in GLU and ASP efflux during a 30 min incubation period and this efflux was sustained or slightly higher during a 15 min recovery period. TMT-stimulated GLU efflux was not altered in aged rats. TMT-induced GLU efflux was significantly reduced by removing extracellular calcium and including 10 microM EGTA in the incubation media. Calcium channel blockers (nifedipine, verapamil, flunarizine, amiloride, neomycin) and MK-801 did not significantly attenuate TMT-induced GLU efflux. Diltiazem (25 microM) produced modest but inconsistent reductions in TMT-induced GLU efflux from brain slices, and significantly inhibited the leakage of lactate dehydrogenase (LDH) from TMT-treated astrocyte cultures. TMT did not increase GLU efflux from glial cultures during a 30 min incubation period, but did significantly elevate GLU efflux during the 15 min recovery period. TMT evoked the release of EAA by both calcium dependent and independent mechanisms in brain slices. TMT at high concentrations also produced a delayed increase in glial GLU efflux. These studies suggest that excitotoxic mechanisms may contribute to TMT-induced neurotoxicity.
三甲基锡（TMT）是一种有毒的烷基锡化合物，已知会在中枢神经系统中导致神经元坏死。本研究检测了TMT对成年和老年（24月龄）大鼠制备的皮质切片中兴奋性氨基酸（EAA）释放的影响。评估了TMT诱导的EAA流出对钙的依赖性，并与其他神经毒性剂进行了比较。还在星形胶质细胞培养模型中评估了TMT的作用，以评估神经胶质对TMT诱导的EAA流出的影响。在30分钟的孵育期内，TMT（10 - 1000微摩尔）引起GLU和ASP流出呈剂量相关增加，并且在15分钟的恢复期内这种流出持续存在或略有升高。老年大鼠中TMT刺激的GLU流出没有改变。通过去除细胞外钙并在孵育培养基中加入10微摩尔EGTA，TMT诱导的GLU流出显著减少。钙通道阻滞剂（硝苯地平、维拉帕米、氟桂利嗪、阿米洛利、新霉素）和MK - 801并没有显著减弱TMT诱导的GLU流出。地尔硫卓（25微摩尔）使脑切片中TMT诱导的GLU流出产生适度但不一致的减少，并显著抑制TMT处理的星形胶质细胞培养物中乳酸脱氢酶（LDH）的泄漏。在30分钟的孵育期内，TMT没有增加神经胶质培养物中的GLU流出，但在15分钟的恢复期内确实显著提高了GLU流出。TMT通过钙依赖性和非依赖性机制在脑切片中引起EAA的释放。高浓度的TMT还使神经胶质GLU流出延迟增加。这些研究表明，兴奋性毒性机制可能导致TMT诱导的神经毒性。
