Schwartz-Bloom R D, Sah R
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
J Neurochem. 2001 Apr;77(2):353-71. doi: 10.1046/j.1471-4159.2001.00274.x.
In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.
在本综述中，我们阐述了γ-氨基丁酸（GABA）神经传递在脑缺血诱导的神经元死亡中所起作用的证据。虽然谷氨酸神经传递在该研究领域已受到广泛关注，但相对较少的研究人员关注缺血诱导的抑制性神经传递的改变。我们对脑缺血对GABA能突触前和突触后靶点的影响进行了综述。缺血的体外和体内模型均已用于测量GABA合成、释放、再摄取、GABA(A)受体表达和活性的变化。已证明由缺血产生的改变GABA神经传递的细胞事件包括Cl(-)梯度的变化、ATP的减少、细胞内Ca(2+)的增加、活性氧的产生以及花生四烯酸和类二十烷酸的积累。增加GABA神经传递的神经保护策略也针对突触的两侧，通过阻止GABA的再摄取和代谢以及用激动剂和变构调节剂增加GABA(A)受体活性来实现。其中一些策略在脑缺血动物模型中相当有效，唯一不良副作用是镇静作用。基于有前景的动物数据，针对特定类型中风的GABA能药物的临床试验正在进行。本综述试图提供对GABA神经传递对脑缺血敏感的机制的理解。此外，我们讨论了GABA神经传递功能障碍如何导致神经元死亡以及GABA能药物如何预防神经元死亡。
