Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling

Wen ZHANG1, Jun-ke SONG1, Rong YAN1, Li LI1, Zhi-yong XIAO2, Wen-xia ZHOU2, Zhen-zhong WANG3, Wei XIAO3, Guan-hua DU1
1 Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2 Department of TCM and Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China
3 State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co, Ltd, Lianyungang 222001, China
Correspondence to: Guan-hua DU:,
DOI: 10.1038/aps.2017.149
Received: 4 August 2017
Accepted: 8 November 2017
Advance online: 15 March 2018


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 μg/mL) or ginkgolides A, B or C (10 μmol/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 iin vivo and in vitro.
Keywords: cerebral ischemia; diterpene ginkgolides; PI3K; Akt; Nrf2; HO-1; CREB; LY294002

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