Dave Kunjan R, Lange-Asschenfeldt Christian, Raval Ami P, Prado Ricardo, Busto Raul, Saul Isabel, Pérez-Pinzón Miguel A
Cerebral Vascular Disease Research Center, Department of Neurology and Neuroscience, University of Miami School of Medicine, Miami, Florida 33101, USA.
J Neurosci Res. 2005 Dec 1;82(5):665-73. doi: 10.1002/jnr.20674.
Excitotoxicity is recognized to play a major role in cerebral ischemia-induced cell death. The main goal of the present study was to define whether our model of ischemic preconditioning (IPC) promotes a shift from excitatory to inhibitory neurotransmission during the test ischemia to diminish metabolic demand during the reperfusion phase. We also determined whether gamma-aminobutyric acid (GABA) played a role in IPC-induced neuroprotection. Ten minutes of cerebral ischemia was produced by tightening the carotid ligatures bilaterally following hypotension. Samples of microdialysis perfusate, representing extracellular fluid, were analyzed for amino acid content by HPLC. IPC promoted a robust release of GABA after lethal ischemia compared with control rats. We also observed that the activity of glutamate decarboxylase (the predominant pathway of GABA synthesis in the brain) was higher in the IPC group compared with control and ischemic groups. Because GABAA receptor up-regulation has been shown to occur following IPC, and GABAA receptor activation has been implicated in neuroprotection against ischemic insults, we tested the hypothesis that GABAA or GABAB receptor activation was neuroprotective during ischemia or early reperfusion by using an in vitro model (organotypic hippocampal slice culture). Administration of the GABAB agonist baclofen during test ischemia and for 1 hr of reperfusion provided significant neuroprotection. We concluded that increased GABA release in preconditioned animals after ischemia might be one of the factors responsible for IPC neuroprotection. Specific activation of GABAB receptor contributes significantly to neuroprotection against ischemia in organotypic hippocampal slices.
兴奋性毒性被认为在脑缺血诱导的细胞死亡中起主要作用。本研究的主要目的是确定我们的缺血预处理（IPC）模型是否能在测试性缺血期间促进从兴奋性神经传递向抑制性神经传递的转变，以减少再灌注期的代谢需求。我们还确定了γ-氨基丁酸（GABA）是否在IPC诱导的神经保护中发挥作用。在低血压后双侧收紧颈动脉结扎线，造成10分钟的脑缺血。通过高效液相色谱法分析代表细胞外液的微透析灌流液样本中的氨基酸含量。与对照大鼠相比，IPC在致死性缺血后促进了GABA的大量释放。我们还观察到，与对照组和缺血组相比，IPC组中谷氨酸脱羧酶（大脑中GABA合成的主要途径）的活性更高。由于已证明IPC后会发生GABAA受体上调，且GABAA受体激活与针对缺血性损伤的神经保护有关，我们通过体外模型（器官型海马切片培养）测试了GABAA或GABAB受体激活在缺血或早期再灌注期间具有神经保护作用的假设。在测试性缺血期间及再灌注1小时内给予GABAB激动剂巴氯芬可提供显著的神经保护作用。我们得出结论，缺血后预处理动物中GABA释放增加可能是IPC神经保护的因素之一。GABAB受体的特异性激活对器官型海马切片中针对缺血的神经保护作用有显著贡献。
