10-O-(N N-Dimethylaminoethyl)-Ginkgolide B Methane-Sulfonate (XQ-1H) Ameliorates Cerebral Ischemia Via Suppressing Neuronal Apoptosis
10-O-(N N-Dimethylaminoethyl)-Ginkgolide B Methane-Sulfonate (XQ-1H) Ameliorates Cerebral Ischemia Via Suppressing Neuronal Apoptosis
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DOI：
10.1016/j.jstrokecerebrovasdis.2021.105987
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发表时间：
2021-07-14
影响因子：
2.5
通讯作者：
Li，Yunman
中科院分区：
文献类型：
--
作者：
Khadankhuu，Bayarmaa;Fei，Yuxiang;Li，Yunman
目的：银杏内酯B甲磺酸盐（10-O-（N-N-二甲氨基乙基）-ginkgolide methane-sulfonate，XQ-1H）是从广泛应用于心脑血管疾病治疗的中药银杏内酯B中分离得到的一种有效的治疗缺血性脑血管疾病的新药。材料与方法：本研究旨在观察XQ-1H对大鼠大脑中动脉闭塞/再灌注（MCAO/R）及缺氧/复氧（OGD/R）诱导的嗜铬细胞瘤（PC-12）细胞凋亡的神经保护作用。结果表明，不同剂量XQ-1H对小鼠肝细胞有明显的抑制作用，（7.8，15.6，31.2mg/kg）可减轻脑梗死和水肿，减轻神经行为功能障碍，改善MCAO/R大鼠脑组织细胞形态。XQ-1H（1 μM、3 μM、10 μM、50 μM、100 μM）孵育可增加细胞活力，对PC-12细胞无毒性作用。XQ-1H在1 μM、10 μM、100 μM浓度下可降低OGD/R诱导的PC-12细胞的乳酸脱氢酶（LDH）活性，抑制细胞凋亡。此外，XQ-1H可抑制caspase-3在体内和体外的活化，并通过激活PI 3 K/Akt信号通路，间接调节凋亡相关蛋白bcl-2和bax的表达。为验证其作用机制，引入PI 3 K/Akt通路抑制剂LY 294002，可下调bcl-2和磷酸化Akt的表达，上调bax的表达，提示XQ-1H可通过激活PI 3 K/Akt通路减轻细胞凋亡。我们的研究结果表明，XQ-1H治疗可以提供对脑缺血诱导的缺血性中风的神经保护作用。通过调节神经元存活和抑制细胞凋亡，在体和离体的再灌注损伤。本研究结果证实XQ-1H可作为一种潜在的治疗缺血性脑卒中的药物。
Objectives:The 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1H) is an effective novel drug for the treatment of ischemic cerebrovascular disease derived from Ginkgolide B, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, whether XQ-1H exerts neuroprotective effect via regulating neuronal apoptosis and the underlying mechanism remain to be elucidated.Materials and methods:This study was aimed to investigate the neuroprotective effect of XQ-1H in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and the oxygen glucose deprivation/reoxygenation (OGD/R) induced neuronal apoptosis on pheochromocytoma (PC-12) cells.Results:The results showed that administration of XQ-1H at different dosage (7.8, 15.6, 31.2 mg/kg) reduced the brain infarct and edema, attenuated the neuro-behavioral dysfunction, and improved cell morphology in brain tissue after MCAO/R in rats. Moreover, incubation with XQ-1H (1 µM, 3 µM, 10 µM, 50 µM, 100 µM) could increase the cell viability, and showed no toxic effect to PC-12 cells. XQ-1H at following 1 µM, 10 µM, 100 µM decreased the lactate dehydrogenase (LDH) activity and suppressed the cell apoptosis in PC-12 cells exposed to OGD/R. In addition, XQ-1H treatment could significantly inhibit caspase-3 activation bothin vivoand in vitro, reciprocally modulate the expression of apoptosis related proteins, bcl-2, and bax via activating PI3K/Akt signaling pathway. For mechanism verification, LY294002, the inhibitor of PI3K/Akt pathway was introduced the expressions of bcl-2 and phosphorylated Akt were down-regulated, the expression of bax was up-regulated, indicating that XQ-1H could alleviate the cell apoptosis through activating the PI3K/Akt pathway.Conclusions:Our findings demonstrated that XQ-1H treatment could provide a neuroprotective effect against ischemic stroke induced by cerebral ischemia/reperfusion injuryin vivoand in vitro through regulating neuronal survival and inhibiting apoptosis. The findings of the study confirmed that XQ-1H could be develop as a potential drug for treatment of cerebral ischemic stroke.