Int J Biol Sci 2022; 18(11):4578-4594. doi:10.7150/ijbs.69892 This issue

Research Paper

Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo

Tangming Peng1,2#, Shuai Li1#, Linlin Liu1, Chao Yang1, Mohd Farhan1, Ligang Chen2, Qiaozhu Su3, Wenhua Zheng1✉

1. Faculty of Health Science, University of Macau, Taipa, Macau, China
2. Department of Neurosurgery, Affiliated Hospital of Southwest Medical University and Neurosurgical Clinical Research Center of Sichuan Province, Luzhou, China
3. Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, United Kingdom
# These authors contributed equally to this study.

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Citation:
Peng T, Li S, Liu L, Yang C, Farhan M, Chen L, Su Q, Zheng W. Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo. Int J Biol Sci 2022; 18(11):4578-4594. doi:10.7150/ijbs.69892. Available from https://www.ijbs.com/v18p4578.htm

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Abstract

Graphic abstract

Ischemic stroke is characterized by the presence of both brain ischemic and reperfusion-induced injuries in the brain, leading to neuronal dysfunction and death. Artemisinin, an FDA-approved antimalarial drug, has been reported to have neuroprotective properties. However, the effect of artemisinin on ischemic stroke is not known. In the present study, we investigated the effect of artemisinin on ischemic stroke using an oxygen-glucose deprivation/reperfusion (OGD/RP) cellular model and a mouse middle cerebral artery occlusion (MCAO) animal model and examined the underlying mechanisms. The obtained results revealed that a subclinical antimalarial concentration of artemisinin increased cell viability and decreased LDH release and cell apoptosis. Artemisinin also attenuated the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Δψm). Importantly, artemisinin attenuated the infarction volume and the brain water content in the MCAO animal model. Artemisinin also improved neurological and behavioural outcomes and restored grasp strength and the recovery of motor function in MCAO animals. Furthermore, artemisinin treatment significantly inhibited the molecular indices of apoptosis, oxidative stress and neuroinflammation and activated the ERK1/2/CREB/BCL-2 signaling pathway. Further validation of the involved signaling pathway by the ERK1/2 inhibitor PD98059 revealed that inhibiting the ERK1/2 signaling pathway or silencing ERK1/2 reversed the neuroprotective effects of artemisinin. These results indicate that artemisinin provides neuroprotection against ischemic stroke via the ERK1/2/CREB/BCL-2 signaling pathway. Our study suggests that artemisinin may play an important role in the prevention and treatment of stroke.

Keywords: Ischemic stroke, artemisinin, neuronal damage, ERK1/2/CREB/BCL-2