Repeated concussion represents a serious health problem as it can result in various brain pathologies, ranging from minor focal tissue injury to severe chronic traumatic encephalopathy. The calcium-dependent protease, calpain, participates in the development of neurodegeneration following concussion, but there is no information regarding the relative contribution of calpain-1 and calpain-2, the major calpain isoforms in the brain. We used a mouse model of repeated concussions, which reproduces most of the behavioral and neuropathological features of the human condition, to address this issue. Deletion of calpain-2 or treatment with a selective calpain-2 inhibitor for 2 weeks prevented most of these neuropathological features. Changes in TAR DNA binding protein 43 (TDP-43) subcellular localization similar to those found in human amyotrophic lateral sclerosis and frontotemporal dementia were also prevented by deletion of calpain-2 or treatment with calpain-2 inhibitor. Our results indicate that a selective calpain-2 inhibitor represents a therapeutic approach for concussion.

反复脑震荡是一个严重的健康问题，因为它可能导致各种脑部病变，从轻微的局灶性组织损伤到严重的慢性创伤性脑病。钙依赖性蛋白酶钙蛋白酶参与脑震荡后神经退行性变的发展，但没有关于大脑中主要钙蛋白酶异构体 calpain-1 和 calpain-2 的相对贡献的信息。我们使用重复脑震荡的小鼠模型来解决这个问题，该模型再现了人类状况的大部分行为和神经病理学特征。删除 calpain-2 或用选择性 calpain-2 抑制剂治疗 2 周可防止大多数这些神经病理学特征。TAR DNA 结合蛋白 43 (TDP-43) 亚细胞定位的变化类似于在人类肌萎缩侧索硬化症和额颞叶痴呆中发现的变化，也可以通过缺失 calpain-2 或用 calpain-2 抑制剂治疗来防止。我们的结果表明，选择性 calpain-2 抑制剂代表了脑震荡的治疗方法。