GABAA receptor activation attenuates excitotoxicity but exacerbates oxygen-glucose deprivation-induced neuronal injury in vitro.
We examined the effects of GABA receptor stimulation on the neuronal death induced by exogenously added excitatory amino acids or combined oxygen-glucose deprivation in mouse cortical cell cultures. Death induced by exposure to NMDA, AMPA, or kainate was attenuated by addition of GABA or the GABAA receptor agonist, muscimol, but not by the GABAB receptor agonist, baclofen. The antiexcitotoxic effect of GABAA receptor agonists was blocked by bicuculline or picrotoxin. In contrast, GABA or muscimol, but not baclofen, markedly increased the neuronal death induced by oxygen-glucose deprivation. Muscimol potentiation of neuronal death was associated with increased glutamate efflux to the bathing medium, and increased cellular 45Ca2+ accumulation; it was blocked by MK-801, but not NBQX, suggesting mediation by NMDA receptors. Bicuculline only weakly attenuated muscimol potentiation of oxygen-glucose deprivation-induced neuronal death, probably because it itself increased this death. Present results raise a note of caution in the proposed use of GABAA receptor stimulation to limit ischemic brain damage in vivo.
Muir
J K
JK
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Lobner
D
D
Monyer
H
H
Choi
D W
DW
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018755:GABA Agonists / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*
D018755:GABA Agonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D009118:Muscimol; D001418:Baclofen; D005947:Glucose; D010100:Oxygen