Calpain as a therapeutic target in traumatic brain injury.
Calpain as a therapeutic target in traumatic brain injury.
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DOI：
10.1016/j.nurt.2009.11.002
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Raghupathi R
中科院分区：
文献类型：
--
作者：
Saatman KE;Creed J;Raghupathi R
钙活化中性蛋白酶家族，钙蛋白酶，似乎在创伤性脑损伤（TBI）后的神经病理事件中起关键作用。在动物的挫伤或弥漫性脑损伤后几分钟至几小时内观察到神经元钙蛋白酶的激活，表明钙蛋白酶是神经元损伤的早期介质。虽然短暂的钙蛋白酶激活触发了许多参与正常生理过程的细胞信号传导和重塑事件，但在多种创伤性脑损伤模型中，创伤产生的持续钙蛋白酶激活与神经元死亡和轴突变性有关。然而，钙蛋白酶激活与神经元死亡之间的因果关系尚不完全清楚。在这方面，关于控制钙蛋白酶活性的内源性调节机制，不同钙蛋白酶异构体的作用，以及受钙蛋白酶影响的体内底物，还有很多有待研究。检测calpain特异性切割的亚膜细胞骨架蛋白α ii -谱蛋白的稳定蛋白水解片段已成为TBI模型中最广泛使用的calpain激活标志物。最近，这些蛋白片段在脑外伤后的脑脊液中被检测到，这促使人们对它们作为脑外伤相关生物标志物的潜在效用产生了兴趣。创伤后钙疼痛的抑制，直接或间接通过与细胞内钙调节相关的靶点，与TBI动物模型中功能和行为缺陷、轴突病理和细胞死亡的减轻有关。本文综述了钙蛋白酶在脑外伤引起的神经病理中的作用，以及钙蛋白酶在急性创伤后期作为治疗靶点的有效性。
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 following either contusive or diffuse brain trauma in animals, suggesting calpains are an early mediator of neuronal damage. While 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. However, the causal relationship between calpain activation and neuronal death is not fully understood. In this respect, 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 αII-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. Posttraumatic inhibition of calpains, either directly or indirectly 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.
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