Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling
Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling
复制标题
二萜银杏内酯通过 PI3K/Akt 信号传导激活 Nrf2 和 CREB，从而保护大鼠免受脑缺血/再灌注损伤。
DOI：
10.1038/aps.2017.149
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发表时间：
2018-08-01
影响因子：
8.2
通讯作者：
Du, Guan-hua
中科院分区：
文献类型：
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作者：
Zhang, Wen;Song, Jun-ke;Du, Guan-hua
二萜银杏内酯葡甲胺注射液（DGMI）是银杏叶提取物的一种治疗性提取物，在我国已用于治疗缺血性脑卒中。银杏内酯A、B和C是DGMI的主要成分。本研究旨在研究DGMI组分在体内和体外对缺血性卒中的神经保护作用。采用大鼠大脑中动脉（MCA）闭塞1.5h再灌注24 h的方法，建立急性脑缺血损伤模型。在再灌注开始时和再灌注后12 h分别静脉注射DGMI（1、3和10 mg/kg）。给予DGMI显著降低大鼠神经功能缺损评分，减少脑梗死体积，并诱导蛋白激酶B（Akt）磷酸化，这促进了核因子-红细胞2相关因子2（Nrf 2）的核转位和存活调节蛋白环AMP反应元件结合蛋白（CREB）的磷酸化。Nrf 2激活导致下游蛋白血红素加氧酶-1（HO-1）的表达。另外，PC 12细胞在体外进行氧-葡萄糖剥夺/再灌注（OGD/R），用DGMI（1、10和20 μ g/mL）或银杏内酯A、B或C（各10 μ mol/L）处理显著减少PC 12细胞死亡，并增加Akt的磷酸化、Nrf 2的核转位和CREB的活化。Nrf 2和CREB的激活可以通过与磷酸肌醇-3-激酶（PI 3 K）抑制剂LY 294002共同处理来逆转。这些观察结果表明，银杏内酯作为一种新的外源性调节剂激活Akt/Nrf 2和Akt/CREB信号通路，保护脑缺血/再灌注（I/R）损伤在体内和体外。
Diterpene ginkgolides meglumine injection (DGMI) is a therapeutic extract of Ginkgo biloba L, which has been used for the treatment of cerebral ischemic stroke in China. Ginkgolides A, B and C are the main components of DGMI. This study was designed to investigate the neuroprotective effects of DGMI components against ischemic stroke in vivo and in vitro. Acute cerebral ischemic injury was induced in rats by occlusion of the middle cerebral artery (MCA) for 1.5 h followed by 24 h reperfusion. The rats were treated with DGMI (1, 3 and 10 mg/kg, iv) at the onset of reperfusion and 12 h after reperfusion. Administration of DGMI significantly decreased rat neurological deficit scores, reduced brain infarct volume, and induced protein kinase B (Akt) phosphorylation, which prompted the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and phosphorylation of the survival regulatory protein cyclic AMP-responsive element binding protein (CREB). Nrf2 activation led to expression of the downstream protein heme oxygenase-1 (HO-1). In addition, PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) in vitro, treatment with DGMI (1, 10 and 20 mu g/mL) or ginkgolides A, B or C (10 mu mol/L for each) significantly reduced PC12 cell death and increased phosphorylation of Akt, nuclear translocation of Nrf2 and activation of CREB. Activation of Nrf2 and CREB could be reversed by co-treatment with a phosphoinositide-3-kinase (PI3K) inhibitor LY294002. These observations suggest that ginkgolides act as novel extrinsic regulators activating both Akt/Nrf2 and Akt/CREB signaling pathways, protecting against cerebral ischemia/reperfusion (I/R) damage in vivo and in vitro.