Attenuation of excitotoxic cell swelling and GABA release by the GABA transport inhibitor SKF 89976A.
Acute excitotoxicity in the chick retina is characterized by cellular swelling and the subsequent selective release of GABA. In order to understand the source of GABA release, embryonic day 15 retina were incubated with 1 mM glutamate for 30 min in the presence or absence of the GABA transport inhibitor SKF 89976A (1-100 microM). SKF 89976A dose-dependently attentuated glutamate-induced GABA release (IC50, 39 microM). Histological examination of retina showed that SKF 89976A greatly reduced cellular swelling caused by glutamate exposure. Interaction of SKF 89976A with glutamate receptors was ruled out as a possible reason for protection vs acute glutamate excitotoxicity, since SKF 89976A had no effect on glutamate receptor-induced 22Na+ influx. In contrast, the NMDA antagonist, MK-801, significantly blocked glutamate-evoked 22NA+ uptake. These studies indicate that reversal of the GABA transporter contributes to the bulk of GABA release during acute excitotoxicity in retina. Further, a net effect of the presence of SKF 89976A during glutamate exposure is reduction in cellular swelling. It is not clear at present if attenuation of swelling is mediated specifically by an interaction with the GABA transporter or by a nonspecific or indirect effect of SKF 89976A.
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854, USA.
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D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D018682:GABA Agents / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D066298:In Vitro Techniques; D007700:Kinetics; D009498:Neurotoxins / Q000633:toxicity*; D009557:Nipecotic Acids / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018682:GABA Agents; D009498:Neurotoxins; D009557:Nipecotic Acids; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D012964:Sodium