中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (12): 1930-1931.doi: 10.4103/1673-5374.169615

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

内质网应激：保护神经元免受再灌注缺血损伤的策略

  

  • 收稿日期:2015-09-28 出版日期:2015-12-30 发布日期:2015-12-30

Attenuation of endoplasmic reticulum stress as a treatment strategy against ischemia/reperfusion injury

Chih-Li Lin*   

  1. Institute of Medicine, Chung Shan Medical University, Taichung,Taiwan, China
  • Received:2015-09-28 Online:2015-12-30 Published:2015-12-30
  • Contact: Chih-Li Lin, Ph.D., dll@csmu.edu.tw.

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摘要：

虽然大脑只占总体量的约2％，但它消耗体内大约20％的氧气，因此，大脑神经元对缺氧极为敏感。在缺血性脑卒中中，血液供应大脑时会有部分损失，由此触发一系列胞内应激事件并最终导致细胞死亡。依据局部缺血损伤的性质，受影响的组织可分为两个主要损伤区域：核心区，这是血流量减少最严重的区域，不论随后是否有再灌注，其内的脑细胞都会快速死亡。与此相反，邻接于核心区域被定义为半影区，其特征在于血流水平比核心区本身稍大。这表明缺血区域的血流迅速恢复或许能够挽救受威胁的组织。如果在显著细胞死亡发生之前恢复半影区的血流量，再灌注过程中也同样会导致额外的缺氧复氧损伤。缺氧复氧可通过触发伴随线粒体功能障碍和随后细胞死亡的活性氧过量产生诱导显著的神经元死亡。特别是糖原合酶激酶3β在缺氧复氧诱导的氧化应激后已与线粒体功能障碍有关。通常情况下，糖原合酶激酶3β可促进存活信号抑制，如胰岛素/胰岛素样生长因子以及Akt。然而，糖原合酶激酶3β可由缺血性损伤激活，从而促进线粒体功能障碍并诱导细胞凋亡。因此，抑制糖原合酶激酶3β被提议作为急性缺血性损伤后的假定治疗策略。虽然糖原合酶激酶3β抑制是对抗缺血性脑卒中的一个理性策略，但其治疗的成功概率仍然受到不良事件和一个相当小的治疗窗的限制。

Abstract:

Brain ischemic stroke is the leading cause of long-lasting neurological disability and death in adults. Although the brain represents only about 2% of the total body mass, it consumes almost 20% of the body's oxygen. For this reason, brain neurons are extremely sensitive to hypoxia. In an ischemic stroke, blood supply to part of the brain is loss that triggers a series of intracellular stress events eventually leading to cell death. Depending on the nature of the ischemic insult, the affected tissue can be classified into two major zones of injury. In the core zone, which is an area with the most severe reduction in blood flow, and within which brain cells undergo rapid cell dies regardless of subsequent reperfusion. In contrast, adjacent to the central core zone is defined as the penumbra zone, characterized by levels of blood flow slightly greater than the core zone itself. Therefore, cell death in the core zone is rapid, whereas cells in the penumbra zone may remain viable for several hours. This indicates prompt restoration of blood flow to an ischemic area may allow threatened tissue to be salvaged. To restore blood flow before major damage occurred, rapidly administration of thrombolytic agents such as tissue-type plasminogen activator (tPA), has now generally be accepted in carefully selected patients with ischemic stroke. However, if blood flow is restored in the penumbra before significant cell death occurs, the process of reperfusion can also causes additional hypoxia-reoxygenation (H/R) damages. It is known H/R can induce significant neuronal death through triggering overproduction of reactive oxygen species (ROS) accompanied with mitochondrial dysfunction and subsequent cell death. In particular, glycogen synthase kinase 3β (GSK3β) has been linked to mitochondrial dysfunction after H/R-induced oxidative stress. GSK3β is a serine-threonine kinase that was first discovered to phosphorylate and inactivate glycogen synthase, an enzyme in the glycogen synthesis pathway. Normally, GSK3βis suppressed by prosurvival signals such as insulin/insulin-like growth factor (IGF) as well as Akt. However, GSK3βis activated by ischemic injury, which promotes the mitochondrial dysfunction and induces apoptosis. Thus, inhibition of GSK3β is proposed as a putative therapeutic strategy after an acute ischemic insult. Although GSK3β inhibition is a rational strategy to combat ischemic stroke, its therapeutic success is limited by the adverse events and a rather small therapeutic window.