Oncotarget

Research Papers:

Ginkgolide K attenuates neuronal injury after ischemic stroke by inhibiting mitochondrial fission and GSK-3β-dependent increases in mitochondrial membrane permeability

Xu Zhou, Hui-Ying Wang, Bin Wu, Cai-Yi Cheng, Wei Xiao, Zhen-Zhong Wang, Yu-Yu Yang, Ping Li _ and Hua Yang

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Oncotarget. 2017; 8:44682-44693. https://doi.org/10.18632/oncotarget.17967

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Abstract

Xu Zhou1,*, Hui-Ying Wang1,*, Bin Wu1,*, Cai-Yi Cheng1, Wei Xiao2, Zhen-Zhong Wang2, Yu-Yu Yang1, Ping Li1 and Hua Yang1

1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

2State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, China

*These authors have contributed equally to this work

Correspondence to:

Ping Li, email: [email protected]

Hua Yang, email: [email protected]

Keywords: ginkgolide K, mitochondrial fission, mitochondrial permeability transition pore, neuron apoptosis, ischemic stroke

Received: December 22, 2016     Accepted: April 27, 2017     Published: May 18, 2017

ABSTRACT

Ginkgolide K (GK) belongs to the ginkgolide family of natural compounds found in Ginkgo biloba leaves, which have been used for centuries to treat cerebrovascular and cardiovascular diseases. We evaluated the protective effects of GK against neuronal apoptosis by assessing its ability to sustain mitochondrial integrity and function. Co-immunoprecipitation showed that Drp1 binding to GSK-3β was increased after an oxygen-glucose deprivation/reperfusion (OGD/R) insult in cultured neuroblastoma cells. This induced Drp1 and GSK-3β translocation to mitochondria and mitochondrial dysfunction, which was attenuated by GK. GK also reduced mitochondrial fission by increasing Drp1 phosphorylation at Ser637 and inhibiting mitochondrial Drp1 recruitment. In addition, GK exposure induced GSK-3β phosphorylation at Ser9 and enhanced the interaction between adenine nucleotide translocator (ANT) and p-GSK-3β. This interaction suppressed the interaction between ANT and cyclophilin D (CypD), which inhibited mitochondrial permeability transition pore (mPTP) opening. Similarly, suppression of mitochondrial fission by Mdivi-1 also inhibited GSK-3β-induced mPTP opening. Treating mice with GK prevented GSK-3β and Drp1 translocation to mitochondria and attenuated mitochondrial dysfunction after middle cerebral artery occlusion. We therefore propose that by inhibiting mitochondrial fission and attenuating mPTP opening, GK exerts neuroprotective effects that mitigate or prevent neuronal damage secondary to ischemic stroke.


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