The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats
The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats
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DOI：
10.1016/j.brainres.2010.02.074
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发表时间：
2010-05-12
期刊：
影响因子：
2.9
通讯作者：
Kobayashi, Hidenori
中科院分区：
文献类型：
--
作者：
Abe, Eiji;Fujiki, Minoru;Kobayashi, Hidenori
热休克蛋白诱导剂香叶基香叶基丙酮（GGA）对缺血性损伤具有细胞保护作用。磷脂酰肌醇-3激酶/Akt（PI 3 K/Akt）被认为是介导神经保护的重要因子。然而，口服GGA后体内大脑中的信号通路仍不清楚。本研究通过测量大鼠大脑中动脉永久性闭塞后脑梗死体积，探讨银杏叶提取物对大鼠大脑中动脉永久性闭塞后脑梗死的影响。我们评估了5-羟基癸酸（5 HD），一种特异性线粒体ATP敏感性钾（mitoK（ATP））通道抑制剂;二氮嗪（DZX），一种选择性mitoK（ATP）通道开放剂和渥曼青霉素（Wort），一种特异性PI 3 K抑制剂对梗死体积的神经保护作用。为了阐明PI 3 K/Akt活化和神经保护之间的关系，我们使用免疫印迹分析来确定在有或没有麦芽汁处理的情况下给予GGA后存在的p-Akt蛋白的量。（缺血前48 h单次口服GGA剂量（800 mg/kg）预处理）通过5 HD、DZX和Wort预处理来预防，这表明选择性mitoK（ATP）通道和PI 3 K/Akt通路可能介导GGA依赖性保护。口服GGA诱导的p-Akt和GGA预处理增强缺血诱导的p-Akt，这两者都被Wort预处理所阻止。这些结果表明，单次口服剂量的GGA诱导p-Akt，并且GGA通过mitoK（ATP）通道开放在针对脑缺血的神经保护中起重要作用。(C)2010爱思唯尔有限公司版权所有。
Previous studies demonstrated the cytoprotective effect of geranylgeranylacetone (GGA), a heat shock protein inducer, against ischemic insult. Phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is thought to be an important factor that mediates neuroprotection. However, the signaling pathways in the brain in vivo after oral GGA administration remain unclear. We measured and compared infarction volumes to investigate the effect of GGA on cerebral infarction induced by permanent middle cerebral artery occlusion in rats. We evaluated the effects of pretreatment with 5-hydroxydecanoate (5HD), a specific mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel inhibitor; diazoxide (DZX), a selective mitoK(ATP) channel opener and wortmannin (Wort), a specific PI3K inhibitor of GGA-induced neuroprotection against infarction volumes. To clarify the relationship between PI3K/Akt activation and neuroprotection, we used immunoblot analysis to determine the amount of p-Akt proteins present after GGA administration with or without Wort treatment Neuroprotective effects of GGA (pretreatment with a single oral GGA dose (800 mg/kg) 48 h before ischemia) were prevented by 5HD, DZX and Wort pretreatment, which indicates that the selective mitoK(ATP) channel and the PI3K/Akt pathway may mediate GGA-dependent protection. Oral GGA-induced p-Akt and GGA pretreatment enhanced ischemia-induced p-Akt, both of which were prevented by Wort pretreatment. These results suggest that a single oral dose of GGA induces p-Akt and that GGA plays an important role in neuroprotection against cerebral ischemia through the mitoK(ATP) channel opening. (C) 2010 Elsevier B.V. All rights reserved.