中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (8): 1239-1244.doi: 10.4103/1673-5374.162755

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

阿托伐他汀对脑缺血再灌注损伤的神经保护:与抑制内质网应激有关

  

  • 收稿日期:2015-02-02 出版日期:2015-08-24 发布日期:2015-08-24

Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress

Jian-wen Yang, Zhi-ping Hu*   

  1. Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • Received:2015-02-02 Online:2015-08-24 Published:2015-08-24
  • Contact: Zhi-ping Hu, M.D., yangjw941168@sina.com.

摘要:

大脑缺血后继发脑缺血再灌注性损伤,内质网应激能启动细胞凋亡,但具体过程中信号通路调节机制目前尚不清楚。作者推测与内质网应激信号通路中蛋白激酶样内质网激酶/翻译起始因子2a通路有关。此验证此假说,在发现大脑中动脉线栓塞法制作局灶性脑缺血再灌注模型大鼠脑组织中蛋白激酶样内质网激酶和caspase-3表达及翻译起始因子2a的磷酸化水平增加,阿托伐他汀灌胃后可明显抑制上述现象,并减小脑梗死体积,改善脑组织超微结构的病理表现;而同时灌胃阿托伐他汀和翻译起始因子2a磷酸化特异性抑制剂Salubrinal后,梗死侧脑组织中翻译起始因子2a的磷酸化及caspase-3表达受到抑制,也能使脑梗死体积明显缩小,改善脑组织超微结构,但对蛋白激酶样内质网激酶表达无明显影响。因而作者认为阿托伐他汀抑制内质网应激而产生神经元保护作用的机制是通过蛋白激酶样内质网激酶/翻译起始因子2a/caspase-3的途径,从而发挥其减轻脑缺血再灌注损伤的作用。

关键词: 神经再生, 神经保护, 蛋白激酶样内质网激酶, 翻译起始因子2a, 内质网应激, caspase-3, 脑梗死, 局灶性脑缺血再灌注, 阿托伐他汀, 细胞凋亡, 氧化应激

Abstract:

Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral
artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway.

Key words: nerve regeneration, neuroprotection, protein kinase-like endoplasmic reticulum kinase, eukaryotic initiation factor 2α, endoplasmic reticulum stress, focal cerebral ischemia/reperfusion, atorvastatin, apoptosis