Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.
Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.
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DOI：
10.3389/fneur.2015.00178
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发表时间：
2015
影响因子：
3.4
通讯作者：
Hook V
中科院分区：
文献类型：
--
作者：
Hook G;Jacobsen JS;Grabstein K;Kindy M;Hook V
尽管有几十年的实验性临床试验，目前还没有治疗创伤性脑损伤（TBI）的药物治疗。这可能是因为改善TBI结果的机制途径尚未被识别和利用。因此，仍然需要寻找新的分子靶点及其候选药物，以找到TBI的新治疗方法。本文综述了半胱氨酸蛋白酶组织蛋白酶B作为TBI潜在的重要药物靶点的支持证据。组织蛋白酶B表达在TBI动物模型中以及在创伤患者中显著上调。重要的是，敲除TBI小鼠中的组织蛋白酶B基因导致TBI引起的行为、病理学和生物标志物缺陷的实质性改善，以及相关损伤模型的改善。在TBI诱导的损伤过程中，组织蛋白酶B可能逃逸溶酶体（其正常的亚细胞位置）进入细胞质或细胞外基质（ECM），其中释放的蛋白水解能力通过坏死、凋亡、自噬和活化的胶质诱导的细胞死亡以及ECM分解和炎症引起破坏。重要的是，组织蛋白酶B的化学抑制剂可有效改善TBI和相关损伤的缺陷，所述损伤包括缺血、脑出血、脑动脉瘤、水肿、疼痛、感染、类风湿性关节炎、癫痫、亨廷顿病、多发性硬化和阿尔茨海默病。抑制剂E64 d在组织蛋白酶B抑制剂中是独特的，因为它是唯一在TBI模型中证明口服有效性并在人类中预先安全使用的化合物，因此它是用于临床前测试和临床化合物开发的极好的工具化合物。这些数据支持的结论是，组织蛋白酶B抑制剂的治疗TBI的药物开发应该加快。
There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM) where the unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington’s disease, multiple sclerosis, and Alzheimer’s disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.