Bax-inhibiting peptide protects glutamate-induced cerebellar granule cell death by blocking Bax translocation
Bax-inhibiting peptide protects glutamate-induced cerebellar granule cell death by blocking Bax translocation
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DOI：
10.1016/j.neulet.2008.12.021
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发表时间：
2009-02-13
影响因子：
2.5
通讯作者：
Taketani, Yuji
中科院分区：
文献类型：
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作者：
Iriyama, Takayuki;Kamei, Yoshimasa;Taketani, Yuji
谷氨酸诱导的兴奋性毒性与各种神经损伤和疾病的发病机制有关。在未成熟动物的脑损伤中，如新生儿缺氧缺血性脑损伤，兴奋性毒性似乎更密切地通过细胞凋亡参与。Bax是Bcl-2家族蛋白的一员，通过从细胞质移位到线粒体和释放促凋亡因子如细胞色素c，在促进细胞凋亡中起关键作用。Bax抑制肽（BIP）是近年来发现的一种新的膜透性肽，它能结合胞浆中的Bax并抑制Bax向线粒体的转运。为了研究在谷氨酸诱导的神经元细胞死亡中靶向Bax易位的新的神经保护策略的可能性，将小脑颗粒神经元（CGN）暴露于谷氨酸（有或没有BIR）。通过MTT测定，用BIP预处理CGN引起谷氨酸诱导的神经元细胞死亡的剂量依赖性减少。BIP显著抑制谷氨酸诱导的TUNEL阳性细胞数量和caspase 3和9活性的增加。此外，亚细胞分级分离后的免疫印迹显示，BIP阻止谷氨酸诱导的Bax易位到线粒体和细胞色素c从线粒体的释放。这些结果表明，能够抑制Bax活性的药物，如BIP，可能会导致未来谷氨酸相关疾病的新药。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Glutamate-induced excitotoxicity has been implicated in the pathogenesis of various neurological damages and disorders. In the brain damage of immature animals such as neonatal hypoxic-ischemic brain injury, the excitotoxicity appears to be more intimately involved through apoptosis. Bax, a member of the Bcl-2 family proteins, plays a key role in the promotion of apoptosis by translocation from the cytosol to the mitochondria and the release of apoptogenic factors such as cytochrome c. Recently, Bax-inhibiting peptide (BIP), a novel membrane-permeable peptide which can bind Bax in the cytosol and inhibit its translocation to the mitochondria, was developed. To investigate the possibility of a new neuroprotection strategy targeting Bax translocation in glutamate-induced neuronal cell death, cerebellar granule neurons (CGNs) were exposed to glutamate with or without BIR Pretreatment of CGNs with BIP elicited a dose-dependent reduction of glutamate-induced neuronal cell death as measured by MTT assay. BIP significantly suppressed both the number of TUNEL-positive cells and the increase in caspases 3 and 9 activities induced by glutamate. In addition, immunoblotting after subcellular fractionation revealed that BIP prevented the glutamate-induced Bax translocation to the mitochondria and the release of cytochrome c from the mitochondria. These results suggest that agents capable of inhibiting Bax activity such as BIP might lead to new drugs for glutamate-related diseases in the future. (C) 2008 Elsevier Ireland Ltd. All rights reserved.