γ-aminobutyric acid-A receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures
The mechanisms by which anesthetics such as isoflurane reduce cell death in rodent models of cerebral ischemia remain incompletely defined. Reduction in glutamate excitotoxicity explains some but not all of isoflurane's neuroprotection. Because isoflurane potentiates γ-aminobutyric acid (GABA) receptor-mediated ion fluxes and GABAA receptor agonists have neuroprotective effects, we hypothesized that GABAA receptors contribute to isoflurane neuroprotection. As a model of cerebral ischemia and recovery, we used rat hippocampal slice cultures. Survival of CA1, CA3, and dentate neurons was examined 2 and 3 days after 1-h combined oxygen-glucose deprivation (OGD) at 37°C. To define the role of GABAA receptors in mediating protection, the effect of 1% isoflurane on cell survival was examined in the presence of the GABAA antagonist bicuculline during OGD. Cell death was measured with propidium iodide fluorescence. Isoflurane and the selective GABAA agonist muscimol (25 μM) reduced cell death after OGD to values similar to slices not exposed to OGD, with the exception that muscimol did not reduce cell death in CA3 neurons 2 days after OGD. The GABAA antagonist bicuculline reduced the neuroprotective effects of isoflurane on hippocampal neurons 2 and 3 days after OGD. We conclude that GABAA receptors contribute to neuroprotection against OGD produced by isoflurane in the hippocampal slice model. Based on this and other studies, it is likely that neuroprotection produced by isoflurane is multifactorial and includes actions at both GABAA and glutamate receptors and possibly other mechanisms.
Bickler, PE; Warner, DS; Stratmann, G; Schuyler, JA
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