Ferulic acid ameliorates cerebral infarction by activating Akt/mTOR/4E-BP1/Bcl-2 anti-apoptotic signaling in the penumbral cortex following permanent cerebral ischemia in rats
Ferulic acid ameliorates cerebral infarction by activating Akt/mTOR/4E-BP1/Bcl-2 anti-apoptotic signaling in the penumbral cortex following permanent cerebral ischemia in rats
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DOI：
10.3892/mmr.2018.9737
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发表时间：
2019-02-01
影响因子：
3.4
通讯作者：
Lee, Yu-Chen
中科院分区：
文献类型：
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作者：
Cheng, Chin-Yi;Kao, Shung-Te;Lee, Yu-Chen
本研究的目的是确定永久性大脑中动脉闭塞（MCAo）发作后立即给予阿魏酸（FerA），然后缺血7天的影响，并探讨蛋白激酶B（Akt）诱导的信号传导在半影皮层的参与。在MCAo发作后，立即以60 mg/kg（FerA-60 mg）、80 mg/kg（FerA-80 mg）或100 mg/kg（FerA-100 mg）的剂量向大鼠静脉内施用FerA。FerA-80 mg和FerA-100 mg有效地改善了永久性脑缺血后7天的脑梗死和神经功能缺损。FerA-80 mg和FerA-100 mg显著上调磷酸化Akt（p-Akt）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）和真核起始因子4 E（eIF 4 E）结合蛋白1（4 E-BP 1）的表达，磷酸化4 E-BP 1（p-4 E-BP 1）/4 E-BP 1和线粒体Bcl-2/Bax比值，并显著下调细胞色素c-，切割的caspase-3-，缺血后7天半暗带皮质中末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记免疫反应细胞。在缺血前30 min给予选择性磷酸肌醇3激酶/Akt信号通路抑制剂LY 294002，可阻断FerA-100 mg对p-Akt、p-mTOR、4 E-BP 1、p-4 E-BP 1和eIF 4 E表达、线粒体Bcl-2/Bax比值的上调作用以及FerA-100 mg对脑梗死的改善作用。以80和100 mg/kg的剂量施用的FerA通过激活Akt诱导的信号传导而对脑缺血产生有益作用。80和100 mg/kg剂量的FerA对线粒体B细胞淋巴瘤-2（Bcl-2）相关X蛋白相关凋亡的影响归因于Akt/mTOR/4 E-BP 1/Bcl-2抗凋亡信号的激活，并最终导致永久性脑缺血后7天半暗带皮质中细胞色素c/caspase-3激活途径的抑制。
The aim of the present study was to determine the effects of ferulic acid (FerA) administered immediately following the onset of permanent middle cerebral artery occlusion (MCAo) and then 7 days of ischemia, and also to explore the involvement of protein kinase B (Akt)-induced signaling in the penumbral cortex. Immediately following the onset of MCAo, FerA was intravenously administered to rats at a dose of 60 mg/kg (FerA-60 mg), 80 mg/kg (FerA-80 mg), or 100 mg/kg (FerA-100 mg). FerA-80 mg and FerA-100 mg effectively ameliorated cerebral infarction and neurological deficits 7 days following permanent cerebral ischemia. FerA-80 mg and FerA-100 mg significantly upregulated the expression of phospho-Akt (p-Akt), phospho-mammalian target of rapamycin (p-mTOR), and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), and the phospho-4E-BP1 (p-4E-BP1)/4E-BP1 and mitochondrial Bcl-2/Bax ratios, and markedly downregulated the levels of cytochrome c-, cleaved caspase-3-, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-immunoreactive cells in the penumbral cortex at 7 days post-ischemia. LY294002, a selective inhibitor of phosphoinositide 3-kinase/Akt signaling, was administered 30 min prior to ischemia, which abrogated the upregulating effects of FerA-100 mg on the expression of p-Akt, p-mTOR, 4E-BP1, p-4E-BP1 and eIF4E, the mitochondrial Bcl-2/Bax ratio and the ameliorating effect of FerA-100 mg on cerebral infarction. FerA administered at doses of 80 and 100 mg/kg exerted beneficial effects against cerebral ischemia by activating Akt-induced signaling. The effects of FerA at doses of 80 and 100 mg/kg on mitochondrial B-cell lymphoma-2 (Bcl-2)-associated X protein-related apoptosis were attributed to the activation of Akt/mTOR/4E-BP1/Bcl-2 anti-apoptotic signaling, and eventually contributed to suppression of the cytochrome c/caspase-3 activation pathway in the penumbral cortex 7 days following permanent cerebral ischemia.