17 β-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats
17 β-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats
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DOI：
10.1111/j.1472-8206.2004.00284.x
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发表时间：
2004-10-01
影响因子：
2.9
通讯作者：
Lee, KS
中科院分区：
文献类型：
--
作者：
Choi, YC;Lee, JH;Lee, KS
本研究旨在评估雌激素在大鼠大脑中动脉（MCA）闭塞 2 小时，然后再灌注 24 小时引起的脑缺血性损伤中的神经保护作用的信号通路。大鼠在 2 小时 MCA 闭塞完成前 24 小时和完成后 5 分钟接受 β-雌二醇（1、4 和 10 mg/kg，腹腔注射）。在左半球的皮质和纹状体中一致观察到脑梗塞区域。 17β-雌二醇显着减少了半影区末端脱氧核苷酸转移酶介导的脱氧尿苷生物素缺口末端标记 (TUNEL) 阳性细胞和 DNA 片段的增加。与这些结果一致，17β-雌二醇显着增加了Akt和环AMP反应元件结合蛋白（CREB），同时缺血区域的Bcl-2蛋白增加，而从10号染色体删除的磷酸酶和张力蛋白同源物（PTEN）磷酸化的升高则随着Bax蛋白和细胞色素c释放的减少而显着减少。 17β-雌二醇对 DNA 片段化、PTEN 磷酸化和 Akt 激活的抑制作用可被 maxi-K 通道阻断剂 iberiotoxin 拮抗。综上所述，17β-雌二醇抑制脑缺血损伤可能归因于 maxi-K 通道开放耦合 PTEN 磷酸化的下调以及 Akt 和 CREB 磷酸化的上调，从而导致 Bcl-2 蛋白增加和 Bax 蛋白和细胞色素 c 释放减少。
This study aimed to assess the signaling pathway of the neuroprotective action of estrogen in the cerebral ischemic injury evoked by subjecting rats to 2-h occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion. Rats received beta-estradiol (1, 4 and 10 mg/kg, i.p.) 24 h before and 5 min after the completion of 2-h MCA occlusion. The cerebral infarct area was consistently observed in the cortex and striatum of the left hemisphere. Increased terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick-end labeling (TUNEL)-positive cells and DNA fragmentation in the penumbral zone were significantly reduced by 17 beta-estradiol. In line with these results, 17 beta-estradiol significantly increased Akt and cyclic AMP response element binding protein (CREB) with increased Bcl-2 protein in the ischemic area, whereas the elevated the phosphatase and tensin homolog deleted from chromosome10 (PTEN) phosphorylation was significantly reduced with decreased Bax protein and cytochrome c release. Inhibition of DNA fragmentation, PTEN phosphorylation, and Akt activation by 17 beta-estradiol were antagonized by iberiotoxin, a maxi-K channel blocker. Taken together, it is suggested that suppression of cerebral ischemic injury by 17 beta-estradiol may be ascribed to the maxi-K channel opening-coupled downregulation of PTEN phosphorylation and upregulation of Akt and CREB phosphorylation with resultant increase in Bcl-2 protein and decrease in Bax protein and cytochrome c release.