gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia

In this review, we present evidence for the role of gamma -aminobutyric aci d (GABA) neurotransmission in cerebral ischemia-induced neuronal death. Whi le glutamate neurotransmission has received widespread attention in this ar ea of study, relatively few investigators have focused on the ischemia-indu ced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GA BAergic synapse. Both in vitro and in vivo models of ischemia have been use d to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have b een shown to alter GABA neurotransmission include changes in the Cl- gradie nt, reduction in ATP, increase in intracellular Ca2+, generation of reactiv e oxygen species, and accumulation of arachidonic acid and eicosanoids. Neu roprotective strategies to increase GABA neurotransmission target both side s of the synapse as well, by preventing GABA reuptake and metabolism and in creasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebra l ischemia, with sedation as the only unwanted side-effect. Based on promis ing animal data, clinical trials with GABAergic drugs are in progress for s pecific types of stroke. This review attempts to provide an understanding o f the mechanisms by which GABA neurotransmission is sensitive to cerebral i schemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.