Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1alpha truncation.
Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1alpha truncation.
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DOI：
10.1016/j.expneurol.2009.04.006
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发表时间：
2009-07
影响因子：
5.3
通讯作者：
Baudry, Michel
中科院分区：
文献类型：
--
作者：
Zhou, Miou;Xu, Wei;Liao, Guanghong;Bi, Xiaoning;Baudry, Michel
关键词：
许多细胞事件参与缺血性神经元死亡，尽管人们普遍认识到谷氨酸受体过度激活是引发因素之一，但要确定那些在由缺氧和缺糖引发的级联反应中起关键作用的事件一直很困难。不同的谷氨酸受体拮抗剂，尤其是那些针对N -甲基 - D -天冬氨酸（NMDA）受体的拮抗剂，在缺氧/缺血动物模型中取得了显著成功；然而，这些拮抗剂在临床试验中失败了。我们先前报道，钙蛋白酶介导的代谢型谷氨酸受体1α（mGluR1α）截断在兴奋性毒性中起关键作用，并且一种由围绕mGluR1α钙蛋白酶切割位点的肽段和人类免疫缺陷病毒（HIV）反式激活调节蛋白（TAT）的肽转导结构域组成的TAT - mGluR1肽对兴奋性毒性具有神经保护作用。在本研究中，我们在新生儿缺氧/缺血的体外和体内模型中测试了这种肽的作用。TAT - mGluR1肽分别防止了培养的海马切片中氧/糖剥夺（OGD）以及新生大鼠中缺氧/缺血（H/I）诱导的神经元死亡。TAT - mGluR1阻断了H/I诱导的mGluR1α降解，但对H/I诱导的血影蛋白降解没有影响，这表明神经保护作用是由于防止了钙蛋白酶介导的mGluR1α截断，而不是由于钙蛋白酶抑制。因此，我们的结果表明，mGluR1α截断在新生儿缺氧/缺血中起关键作用，阻断这一事件可能防止许多下游细胞毒性级联反应的激活。与谷氨酸受体拮抗剂和一般的钙蛋白酶抑制剂相比，TAT - mGluR1可能具有有限的副作用。
Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-D-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1α (mGluR1α) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1α and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1α degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1α truncation and not to calpain inhibition. Our results therefore suggest that mGluR1α truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.
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