Cathepsin B Contributes to Traumatic Brain Injury-Induced Cell Death Through a Mitochondria-Mediated Apoptotic Pathway
Cathepsin B Contributes to Traumatic Brain Injury-Induced Cell Death Through a Mitochondria-Mediated Apoptotic Pathway
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DOI：
10.1002/jnr.22453
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发表时间：
2010-10-01
影响因子：
4.2
通讯作者：
Tao, Lu-Yang
中科院分区：
文献类型：
--
作者：
Luo, Cheng-Liang;Chen, Xi-Ping;Tao, Lu-Yang
据报道，溶酶体蛋白酶在缺血性和兴奋毒性神经元细胞死亡中起重要作用。我们以前曾报道过创伤性脑损伤后组织蛋白酶B表达显著增加。本研究旨在研究选择性组织蛋白酶B抑制剂（CBI）[N-L-3-trans-prolcarbamoyloxirane-2-carbonyl）-L-isoleucyl-L-proline]对我们模型中细胞死亡和行为缺陷的影响。我们用碘化丙啶（PI）和抗组织蛋白酶B双标记脑切片中受损细胞，检测组织蛋白酶B酶活性水平及其表达。结果表明，TBI诱导的组织蛋白酶B成熟形式增加相关的酶活性升高，表明组织蛋白酶B可能在TBI诱导的细胞损伤中起作用。发现PI标记神经元特异性核标记物NeuN阳性的细胞，而PI标记的GFAP阳性细胞较少，表明神经元对TBI诱导的细胞死亡更敏感。此外，我们发现，预处理与CBI显着衰减TBI诱导的细胞死亡，病变体积，运动和认知功能障碍。为了分析组织蛋白酶B在细胞死亡信号通路中的作用机制，我们通过电泳、Bcl-2/Bax蛋白表达水平、Bid切割、细胞色素c释放和caspase-3激活评估了DNA片段化。结果表明，组织蛋白酶B有助于TBI诱导的细胞死亡，通过目前的程序性细胞坏死和细胞凋亡介导的途径。(C)2010 Wiley-Liss，Inc.
It has been reported that lysosomal proteases play important roles in ischemic and excitotoxic neuronal cell death. We have previously reported that cathepsin B expression increased remarkably after traumatic brain injury (TBI). The present study sought to investigate the effects of a selective cathepsin B inhibitor (CBI) [N-L-3-trans-prolcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline] on cell death and behavioral deficits in our model. We examined the levels of cathepsin B enzymatic activity and its expression by double labelling damaged cells in the brain slice with propidium iodide (PI) and anticathepsin B. The results showed an elevated enzymatic activity associated with TBI-induced increase in a mature form of cathepsin B, suggesting that cathepsin B may play a role in TBI-induced cell injury. PI was found to label cells positive for the neuronal-specific nuclear marker NeuN, whereas fewer GFAP-positive cells were labelled by PI, suggesting that neurons are more sensitive to cell death induced by TBI. Additionally, we found that pretreatment with CBI remarkably attenuated TBI-induced cell death, lesion volume, and motor and cognitive dysfunction. To analyze the mechanism of action of cathepsin B in the cell death signaling pathway, we assessed DNA fragmentation by electrophoresis, BcI-2/Bax protein expression levels, Bid cleavage, cytochrome c release, and caspase-3 activation. The results imply that cathepsin B contributes to TBI-induced cell death through the present programmed cell necrosis and mitochondria-mediated apoptotic pathways. (C) 2010 Wiley-Liss, Inc.