Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury
Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury
复制标题
抑制FOXO3a/BIM信号通路有助于丹酚酸A对脑缺血/再灌注损伤的保护作用。
DOI：
10.1016/j.apsb.2019.01.010
复制
发表时间：
2019-05-01
影响因子：
14.5
通讯作者：
Du, Guanhua
中科院分区：
文献类型：
--
作者：
Song, Junke;Zhang, Wen;Du, Guanhua
丹参酸A（Salvioleticacid A，Sa 1A）是从中药丹参（Salvia miltiorrhiza Bunge）中提取的有效成分。FOXO 3a信号通路在缺血诱导的细胞凋亡中起着重要的调节作用。然而，没有关于Sa 1A对FoxO 3a的调节作用的信息。为探讨Sa 1A的抗脑缺血作用及其机制，本实验采用SH-SY 5 Y细胞和Sprague道利大鼠，分别建立氧糖剥夺/复氧（OGD/R）和大脑中动脉闭塞/再灌注（MCAO/R）损伤模型。使用特异性抑制剂LY 294002鉴定所涉及的途径。结果表明，Sa 1A浓度依赖性地抑制OGD/R损伤引发的细胞活力丧失。在MCAO/R大鼠中，Sa 1A减少脑梗死，降低脑水肿，改善神经功能，并抑制神经元凋亡，这些都通过磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）特异性抑制剂LY 294002的治疗而减弱。Sa 1A时间和浓度依赖性地上调蛋白激酶B（AKT）及其下游蛋白FOXO 3a的磷酸化水平。此外，在体内和体外，Sa 1A抑制FOXO 3a的核转位，这也被LY 294002逆转。上述结果表明，Sa 1A至少部分地通过AKT/FOXO 3a/BIM途径对抗缺血/再灌注损伤。(C)2019年中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Salvianolic acid A (Sa1A) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box 03a (FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of Sa1A on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of Sa1A, SH-SY5Y cells and Sprague Dawley rats were applied, which were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/ reperfusion (MCAO/R) injuries, respectively. The involved pathway was identified using the specific inhibitor LY294002. Results showed that Sa1A concentration-dependently inhibited OGD/R injury triggered cell viability loss. Sa1A reduced cerebral infarction, lowered brain edema, improved neurological function, and inhibited neuron apoptosis in MCAO/R rats, which were attenuated by the treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) specific inhibitor LY294002. Sa1A time- and concentration-dependently upregulated the phosphorylation levels of protein kinase B (AKT) and its downstream protein FOXO3a. Moreover, the nuclear translocation of FOXO3a was inhibited by Sa1A both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that Sa1A fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.