title: Selective gamma-aminobutyric acid type A receptor antagonism reverses isoflurane ischemic neuroprotection.
abstract: BACKGROUND
  Isoflurane provides protection against severe forebrain ischemia in the rat. The authors hypothesized that this is attributable to interaction with the gamma-aminobutyric acid type A (GABAA) receptor resulting in altered time to onset of ischemic hippocampal depolarization.
  
  
  METHODS
  Organotypic hippocampal slices were subjected to oxygen-glucose deprivation in the presence of isoflurane and combinations of GABAA (bicuculline) and GABAB (phaclofen) receptor antagonists. Cell death was measured. Rats were subjected to severe forebrain ischemia while anesthetized with fentanyl-nitrous oxide or 1.4% isoflurane. In the isoflurane group, rats also received intravenous bicuculline (0, 1, or 2 mg/kg). Neurologic and histologic outcomes and time to depolarization were assessed.
  
  
  RESULTS
  In slices, 2% isoflurane caused near-complete protection against oxygen-glucose deprivation. This was unaffected by coadministration of phaclofen but largely reversed by bicuculline. The GABAA agonist muscimol was also protective, having an effect equivalent to 1% isoflurane. In rats, isoflurane (0 mg bicuculline) improved neurologic and histologic outcome versus fentanyl-nitrous oxide (CA1 percentage of alive neurons: fentanyl-nitrous oxide, 15 +/- 7; isoflurane, 61 +/- 24). The isoflurane effect was reversed in a dose-dependent manner by bicuculline (CA1 percentage alive: 1 mg/kg, 44 +/- 22; 2 mg/kg, 21 +/- 15). Time to depolarization was delayed with isoflurane versus fentanyl-nitrous oxide (137 vs. 80 s) but was not affected by bicuculline (149 s). In contrast, postischemic time to repolarization was more rapid with fentanyl-nitrous oxide or isoflurane plus bicuculline versus isoflurane alone.
  
  
  CONCLUSIONS
  These studies are consistent with the hypothesis that the GABAA receptor serves as a major site of action for isoflurane neuroprotection both in vitro and in vivo. However, the mechanism by which this interaction confers in vivo protection cannot be attributed to effects on the duration of ischemic depolarization.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Hazem
authors.initials: H
authors.lastname: Elsersy
authors.forename: Javier
authors.initials: J
authors.lastname: Mixco
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.forename: Robert D
authors.initials: RD
authors.lastname: Pearlstein
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007530:Isoflurane / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology
chemical_list: D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D007530:Isoflurane