Abe Kazuho, Abe Yuzuru, Saito Hiroshi
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Brain Res. 2003 Nov 14;990(1-2):165-71. doi: 10.1016/s0006-8993(03)03454-1.
We investigated the effect of agmatine on cell viability of rat cerebellar granule neurons in a high-K+ (27.5 mM) medium. Exposure of cultured rat cerebellar granule neurons to agmatine (200-800 microM) resulted in a significant decrease in cell viability. Agmatine-induced neuronal death began to occur 6-12 h after addition, and gradually progressed. The agmatine neurotoxicity was attenuated by N-methyl-D-aspartate (NMDA) receptor antagonists and by enzymatic degradation of L-glutamate with glutamic pyruvic transaminase. Furthermore, a significant increase in extracellular L-glutamate concentration was detected before cell death occurred. In addition, agmatine-induced glutamate release and cell death were both blocked by pretreatment with botulinum toxin C, which is known to specifically inhibit the exocytosis. The agmatine neurotoxicity was not observed when extracellular K+ concentration was lower (10 mM). These results suggest that agmatine induces glutamate release through the exocytosis and thereby causes NMDA receptor-mediated neuronal death in conditions in which extracellular K+ concentrations are elevated.
我们研究了胍丁胺对处于高钾（27.5 mM）培养基中的大鼠小脑颗粒神经元细胞活力的影响。将培养的大鼠小脑颗粒神经元暴露于胍丁胺（200 - 800 microM）会导致细胞活力显著下降。胍丁胺诱导的神经元死亡在添加后6 - 12小时开始发生，并逐渐进展。胍丁胺的神经毒性可被N - 甲基 - D - 天冬氨酸（NMDA）受体拮抗剂以及用谷丙转氨酶对L - 谷氨酸进行酶促降解所减弱。此外，在细胞死亡发生前检测到细胞外L - 谷氨酸浓度显著升高。另外，胍丁胺诱导的谷氨酸释放和细胞死亡均被肉毒杆菌毒素C预处理所阻断，已知肉毒杆菌毒素C可特异性抑制胞吐作用。当细胞外钾离子浓度较低（10 mM）时未观察到胍丁胺的神经毒性。这些结果表明，在细胞外钾离子浓度升高的情况下，胍丁胺通过胞吐作用诱导谷氨酸释放，从而导致NMDA受体介导的神经元死亡。
