ABSTRACT
Inhibitory glutamate and γ-amino-butyric acid (GABA) ergic synapses are present in high concentrations on cortical neurons (1) and found in lesser density in basal ganglia and cerebellum, but lacking in white matter (2). There is ample evidence that cerebral ischemia impairs GABAergic neurotransmission (3): downregulation of GABA receptors in the hippocampus and cerebral cortex can be observed as early as 30 minutes after transient global ischemia (4), and inhibitory postsynaptic potentials disappear earlier than excitatory postsynaptic potentials in hippocampal cornu ammonis section 1 (CA1) pyramidal neurons of rats subjected to cerebral ischemia (5). These alterations of GABA transmission are accompanied or even may be the cause of various cellular events including changes in the Cl− gradient, increase in intracellular Ca2+ concentration, reduction of ATP, and generation of reactive oxygen species, to name a few, which lead to synaptic disruption that can be demonstrated at the microscopic or ultrastructural level before the neuronal somata are disintegrated (6,7). The early disruption of GABAergic transmission formed the rationale for studies of neuroprotection by GABAergic drugs, which were successful in animal models providing additional evidence for the role of this transmitter system in the evolution of ischemic neuronal damage (3). However, a first clinical trial with the GABA modulator clomethiazole has not proven a convincing benefit of this neuroprotective strategy (8).
