Reversed operation of glutamate transporter GLT-1 is crucial to the development of preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures

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. (C) 2004 Wiley-Liss, Inc.