Molecular mechanism(s) of ischemic neuronal injury: The role of excitatory amino acid neurotransmitters and receptors.

摘要

Transient cerebral ischemia observed in patients with cardiac arrest and then successfully resuscitated or induced experimentally in animals, causes irreversible injury in certain populations of neurons. The CA1 pyramidal cells in the hippocampus are among the most sensitive neurons to ischemia. Using a rat forebrain ischemia model and a microdialysis technique, I examined the relevance of elevated extracellular concentrations of excitatory neurotransmitters (ENT) to selective neuronal injury.; Excessive activation of ENT receptors by ischemia-induced ENT release, and a subsequent influx of calcium has been suggested as a principal cause of ischemic neuronal injury. However the extracellular ENT levels return to baseline shortly after reperfusion. Therefore the question of whether there is any late rise of ENT during reperfusion to account for irreversible neuronal injury was examined. Secondly, hypothermia is known to attenuate ischemic neuronal injury. To define the role of glutamate in selective neuronal injury, the question of whether hypothermic protection is mediated by reduced glutamate release during ischemia was examined. Thirdly, neuronal protection by transection of fimbria-fornix, but not the perforant or the Schaffer collateral pathways, 10 to 14 days prior to the induction of ischemia has been reported in our laboratory. Therefore the relationship between ischemia-induced ENT release and CA1 neuronal injury in deafferented hippocampi was assessed. Lastly, the role of AMPA receptors in selective neuronal injury was studied by administration of NBQX, an AMPA antagonist.; I found that (a) there is no secondary rise of glutamate during reperfusion to account for selective neuronal injury, (b) neuronal injury is largely independent of ischemia-induced glutamate release, and (c) blockade of AMPA receptors as late as 12 hours after cerebral reperfusion when extracellular glutamate levels were at baseline protected against ischemic neuronal injury. I concluded that ischemia-induced glutamate release, a presynaptic event, is not responsible for delayed neuronal death. Instead, post-synaptic receptor modification triggered by ischemia and persisting through reperfusion (i.e. alteration of receptor sensitivity) may account for the mechanism of cell injury.