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

Abstract 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. © 2004 Wiley‐Liss, Inc.