Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, Kentucky 40536-0509, USA.
Neurotherapeutics. 2010 Jan;7(1):31-42. doi: 10.1016/j.nurt.2009.11.002.
The family of calcium-activated neutral proteases, calpains, appears to play a key role in neuropathologic events following traumatic brain injury (TBI). Neuronal calpain activation has been observed within minutes to hours after either contusive or diffuse brain trauma in animals, suggesting that calpains are an early mediator of neuronal damage. Whereas transient calpain activation triggers numerous cell signaling and remodeling events involved in normal physiological processes, the sustained calpain activation produced by trauma is associated with neuron death and axonal degeneration in multiple models of TBI. Nonetheless, the causal relationship between calpain activation and neuronal death is not fully understood. Much remains to be learned regarding the endogenous regulatory mechanisms for controlling calpain activity, the roles of different calpain isoforms, and the in vivo substrates affected by calpain. Detection of stable proteolytic fragments of the submembrane cytoskeletal protein alphaII-spectrin specific for cleavage by calpains has been the most widely used marker of calpain activation in models of TBI. More recently, these protein fragments have been detected in the cerebrospinal fluid after TBI, driving interest in their potential utility as TBI-associated biomarkers. Post-traumatic inhibition of calpains, either direct or indirect through targets related to intracellular calcium regulation, is associated with attenuation of functional and behavioral deficits, axonal pathology, and cell death in animal models of TBI. This review focuses on the current state of knowledge of the role of calpains in TBI-induced neuropathology and effectiveness of calpain as a therapeutic target in the acute post-traumatic period.
钙激活中性蛋白酶家族（calpains）似乎在创伤性脑损伤（TBI）后的神经病理事件中发挥关键作用。在动物的挫伤或弥漫性脑创伤后几分钟到几小时内，观察到神经元 calpain 激活，这表明 calpains 是神经元损伤的早期介质。虽然短暂的 calpain 激活触发了许多参与正常生理过程的细胞信号转导和重塑事件，但创伤引起的持续 calpain 激活与多种 TBI 模型中的神经元死亡和轴突退化有关。尽管如此，calpain 激活与神经元死亡之间的因果关系尚未完全阐明。关于控制 calpain 活性的内源性调节机制、不同 calpain 同工型的作用以及 calpain 影响的体内底物，仍有许多需要了解。检测针对 calpain 切割的亚膜细胞骨架蛋白 alphaII- spectrin 的稳定蛋白水解片段一直是 TBI 模型中 calpain 激活的最广泛使用的标志物。最近，这些蛋白片段在 TBI 后也在脑脊液中被检测到，这引起了人们对其作为 TBI 相关生物标志物的潜在应用的兴趣。创伤后 calpain 的直接或间接抑制（通过与细胞内钙调节相关的靶点）与动物 TBI 模型中的功能和行为缺陷、轴突病理学和细胞死亡的减轻有关。这篇综述重点介绍了目前对 calpains 在 TBI 诱导的神经病理学中的作用以及 calpain 作为急性创伤后治疗靶点的有效性的认识。
