Kawahara Koichi, Kosugi Tatsuro, Tanaka Motoki, Nakajima Takayuki, Yamada Takeshi
Laboratory of Cellular Cybernetics, Graduate School of Information Science and Technology, Hokkaido University, Sapporo 060-0814, Japan.
Glia. 2005 Feb;49(3):349-59. doi: 10.1002/glia.20114.
Sublethal ischemia leads to increased tolerance against subsequent prolonged cerebral ischemia in vivo. In the present study, we investigated the roles of the astrocytic glutamate (Glu) transporter GLT-1 in preconditioning (PC)-induced neuronal ischemic tolerance in cortical neuron/astrocyte co-cultures. Ischemia in vitro was simulated by subjecting cultures to both oxygen and glucose deprivation (OGD). A sublethal OGD (PC) increased the survival rate of neurons significantly when cultures were exposed to a lethal OGD 24 h later. The extracellular concentration of Glu increased significantly during PC, and treatment with an inhibitor of N-methyl-D-actetate (NMDA) receptors significantly reversed the PC-induced ischemic tolerance of neurons, suggesting that the increase in extracellular concentration of Glu during PC was critical to the development of PC-induced neuronal ischemic tolerance via the activation of NMDA receptors. Treatment with a GLT-1 blocker during PC suppressed this increase in Glu significantly, and antagonized the PC-induced neuronal ischemic tolerance. This study suggested that the reversed operation of GLT-1 was crucial to the development of neuronal ischemic tolerance.
亚致死性缺血可导致体内对随后延长的脑缺血的耐受性增加。在本研究中，我们研究了星形胶质细胞谷氨酸（Glu）转运体GLT-1在皮层神经元/星形胶质细胞共培养物中预处理（PC）诱导的神经元缺血耐受性中的作用。通过使培养物遭受氧和葡萄糖剥夺（OGD）来模拟体外缺血。当培养物在24小时后暴露于致死性OGD时，亚致死性OGD（PC）显著提高了神经元的存活率。PC期间细胞外Glu浓度显著增加，用N-甲基-D-天冬氨酸（NMDA）受体抑制剂处理可显著逆转PC诱导的神经元缺血耐受性，这表明PC期间细胞外Glu浓度的增加对于通过激活NMDA受体来发展PC诱导的神经元缺血耐受性至关重要。在PC期间用GLT-1阻滞剂处理可显著抑制Glu的这种增加，并拮抗PC诱导的神经元缺血耐受性。本研究表明，GLT-1的反向运作对于神经元缺血耐受性的发展至关重要。
