Muir J K, Lobner D, Monyer H, Choi D W
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Cereb Blood Flow Metab. 1996 Nov;16(6):1211-8. doi: 10.1097/00004647-199611000-00015.
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.
我们研究了γ-氨基丁酸（GABA）受体刺激对小鼠皮质细胞培养物中外源性添加兴奋性氨基酸或联合氧-葡萄糖剥夺诱导的神经元死亡的影响。暴露于N-甲基-D-天冬氨酸（NMDA）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）或红藻氨酸诱导的死亡，通过添加GABA或GABAA受体激动剂蝇蕈醇而减弱，但GABAB受体激动剂巴氯芬则无此作用。GABAA受体激动剂的抗兴奋毒性作用被荷包牡丹碱或印防己毒素阻断。相反，GABA或蝇蕈醇，而非巴氯芬，显著增加了氧-葡萄糖剥夺诱导的神经元死亡。蝇蕈醇对神经元死亡的增强作用与谷氨酸向培养液中的外流增加以及细胞45Ca2+积累增加有关；它被MK-801阻断，但未被NBQX阻断，提示由NMDA受体介导。荷包牡丹碱仅微弱减弱蝇蕈醇对氧-葡萄糖剥夺诱导的神经元死亡的增强作用，可能是因为它本身增加了这种死亡。目前的结果对提议在体内使用GABAA受体刺激来限制缺血性脑损伤提出了警示。
