Ischemic stroke is characterized by the simultaneous injury caused by cerebral ischemia and reperfusion in the brain, resulting in neuronal dysfunction and death. Artemisinin, as a safe FDA-approved antimalarial drug, has been reported with neuroprotective properties. However, the effect of artemisinin on ischemic stroke remains unknown. 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. According to the present results, subclinical antimalarial concentrations of artemisinin increased cell viability, decreased LDH release and apoptosis. Artemisinin also evidently decreased 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 behavioral 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. Altogether, these results present that artemisinin provides neuroprotection against ischemic stroke via the ERK1/2/CREB/BCL-2 signaling pathway. Our study proves that artemisinin may play an important role in the prevention and treatment of stroke.

Supported by NFSC (31771128 and 31371088), FDCT (0127/2019/A3, 0113/2018/A3 and 0038/2020/AMJ), Guangdong Provincial Funding Committee for Basic and Applied Fundamental Research (2022-Natural Science Foundation), University of Macau (File No. MYRG2018-00134-FHS and MYRG2020-00158-FHS). *Corresponding Author