INHIBITION OF PROTEOLYSIS PROTECTS HIPPOCAMPAL-NEURONS FROM ISCHEMIA
INHIBITION OF PROTEOLYSIS PROTECTS HIPPOCAMPAL-NEURONS FROM ISCHEMIA
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DOI：
10.1073/pnas.88.16.7233
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发表时间：
1991-08-01
影响因子：
11.1
通讯作者：
LYNCH, G
中科院分区：
文献类型：
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作者：
LEE, KS;FRANK, S;LYNCH, G
短暂性脑缺血后几分钟内，细胞骨架蛋白发生强烈的蛋白水解，这可能是由于钙敏感蛋白酶（钙蛋白酶）的激活。这种蛋白水解事件发生在神经元变性的明显迹象之前，在选择性神经元脆弱的区域中最明显，并且可能对细胞功能的完整性产生重大影响。目前的研究表明：（i）蛋白水解增强的早期阶段是对缺氧的直接反应，而不是缺血的其他作用，（ii）有可能间接抑制对缺血的体内蛋白水解反应，（iii）蛋白水解的抑制与神经元死亡程度的显著降低有关，和（iv）受保护的神经元表现出正常表现的电生理反应，并保持其表达长时程增强的能力，长时程增强是一种被认为与记忆功能有关的生理可塑性形式。这些观察结果表明，钙激活的蛋白水解是缺血后神经退行性反应的重要组成部分，靶向这种反应可能是一种可行的治疗策略，用于保护脆弱神经元的结构和功能。
Intense proteolysis of cytoskeletal proteins occurs in brain within minutes of transient ischemia, possibly because of the activation of calcium-sensitive proteases (calpains). This proteolytic event precedes overt signs of neuronal degeneration, is most pronounced in regions of selective neuronal vulnerability, and could have significant consequences for the integrity of cellular function. The present studies demonstrate that (i) the early phase of enhanced proteolysis is a direct response to hypoxia rather than other actions of ischemia, (ii) it is possible to pharmacologically inhibit the in vivo proteolytic response to ischemia, (iii) inhibition of proteolysis is associated with a marked reduction in the extent of neuronal death, and (iv) protected neurons exhibit normal-appearing electrophysiological responses and retain their capacity for expressing long-term potentiation, a form of physiological plasticity thought to be involved in memory function. These observations indicate that calcium-activated proteolysis is an important component of the post-ischemic neurodegenerative response and that targeting this response may be a viable therapeutic strategy for preserving both the structure and function of vulnerable neurons.