gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia.
In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.
Schwartz-Bloom
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Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. schwa001@duke.edu
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism; D001569:Benzodiazepines / Q000627:therapeutic use; D001925:Brain Damage, Chronic / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology* / Q000628:therapy; D002118:Calcium / Q000378:metabolism; D002144:Callithrix; D002642:Chick Embryo; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018756:GABA Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply / Q000473:pathology; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000473:pathology; D007473:Ion Channels / Q000378:metabolism; D017136:Ion Transport; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018118:Chloride Channels; D002712:Chlorides; D015777:Eicosanoids; D018755:GABA Agonists; D018756:GABA Antagonists; D007473:Ion Channels; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D016718:Arachidonic Acid; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D002118:Calcium