Original articles
Junke Song, Wen Zhang, Jinhua Wang, Haiguang Yang, Qimeng Zhou, Haigang Wang, Li Li, Guanhua Du. Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury[J]. Acta Pharmaceutica Sinica B, 2019, 9(3): 505-515

Inhibition of FOXO3a/BIM signaling pathway contributes to the protective effect of salvianolic acid A against cerebral ischemia/reperfusion injury
Junke Songa,b, Wen Zhanga,b, Jinhua Wanga,b, Haiguang Yanga,b, Qimeng Zhoua,b, Haigang Wanga,b, Li Lia,b, Guanhua Dua,b
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
b Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Salvianolic acid A (SalA) is an effective compound extracted from traditional Chinese medicine Salvia miltiorrhiza Bunge. The Forkhead box O3a (FOXO3a) signaling pathway plays crucial roles in the modulation of ischemia-induced cell apoptosis. However, no information about the regulatory effect of SalA on FoxO3a is available. To explore the anti-cerebral ischemia effect and clarify the therapeutic mechanism of SalA, 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 SalA concentration-dependently inhibited OGD/R injury triggered cell viability loss. SalA 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. SalA 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 SalA both in vivo and in vitro, which was also reversed by LY294002. The above results indicated that SalA fought against ischemia/reperfusion damage at least partially via the AKT/FOXO3a/BIM pathway.
Key words:    Salvianolic acid A    Ischemia reperfusion    FOXO3a    BIM    Neuroprotection   
Received: 2018-10-13     Revised:
DOI: 10.1016/j.apsb.2019.01.010
Funds: This work was supported by grants from National Natural Science Foundation of China (No. 81603100) and the CAMS Innovation Fund for Medical Sciences (2017-I2M-1-010, China).
Corresponding author: Guanhua Du     Email:dugh@imm.ac.cn
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Junke Song
Wen Zhang
Jinhua Wang
Haiguang Yang
Qimeng Zhou
Haigang Wang
Li Li
Guanhua Du

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