Artemether confers neuroprotection on cerebral ischemic injury through stimulation of the Erk1/2-P90rsk-CREB signaling pathway
Shuai Li,
Tangming Peng,
Xia Zhao,
Marta Silva,
Linlin Liu,
Wenshu Zhou,
Ligang Chen,
Wenhua Zheng
Affiliations
Shuai Li
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
Tangming Peng
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China; Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
Xia Zhao
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
Marta Silva
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
Linlin Liu
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
Wenshu Zhou
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
Ligang Chen
Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou, China; Corresponding author. Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou, China.
Wenhua Zheng
Center of Reproduction, Development & Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China; Zhuhai UM Science & Technology Research Institute, Zhuhai, China; Corresponding author. Faculty of Health Sciences, University of Macau Room, 3057, Building E12, Taipa, Macau.
Ischemic stroke is one of the leading causes of death and disability among adults. Despite the economic burden of the disease, available treatment options are still very limited. With the exception of anti-thrombolytics and hypothermia, current therapies fail to reduce neuronal injury, neurological deficits and mortality rates, suggesting that the development of novel and more effective therapies against ischemic stroke is urgent. In the present study, we found that artemether, which has been used in the clinic as an anti-malarial drug, was able to improve the neurological deficits, attenuate the infarction volume and the brain water content in a middle cerebral artery occlusion (MCAO) animal model. Furthermore, artemether treatment significantly suppressed cell apoptosis, stimulated cell proliferation and promoted the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), P90rsk and cAMP responsive element-binding protein (CREB). Artemether protective effect was attenuated by PD98059, an ERK1/2 inhibitor, administration. Similarly, in oxygen-glucose deprivation/reperfusion (OGD/RP) cell models, artemether pre-treatment induced the suppression of the intracellular ROS, the down-regulation of LDH activity, the reduction of caspase 3 activity and of the apoptosis cell rate and reversed the decrease of mitochondrial membrane potential. As with MCAO animal model, artemether promoted the activation of Erk1/2-P90rsk-CREB signaling pathway. This effect was blocked by the inhibition or knock-down of ERK1/2. The present study provides evidences of the neuroprotective effect of artemether unravelling its potential as a new therapeutic candidate for the prevention and treatment of stroke.
