Icariin improves oxidative stress injury during ischemic stroke via inhibiting mPTP opening

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2024-06, Vol.30 (1), p.77-14
• Main Authors: Zhou, Zhiyong, Li, Weili, Ni, Lu, Wang, Tianlun, Huang, Yan, Yu, Yuanqi, Hu, Mingxin, Liu, Yinling, Wang, Jin'e, Huang, Xiaofei, Wang, Yanyan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cell Survival - drug effects; Cerebral ischemia-reperfusion; Disease Models, Animal; Flavonoids - pharmacology; Flavonoids - therapeutic use; Hydrogen Peroxide - metabolism; Icariin; Ischemic stroke; Ischemic Stroke - drug therapy; Ischemic Stroke - etiology; Ischemic Stroke - metabolism; Male; Membrane Potential, Mitochondrial - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial permeability transition pore; Mitochondrial Permeability Transition Pore - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidative Stress - drug effects; PC12 Cells; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; ROS
• ISSN: 1528-3658; 1076-1551; 1528-3658
• DOI: 10.1186/s10020-024-00847-2

Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear. PC-12 cells were treated with 200 µM H O for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting. In vitro: ICT effectively improved H O -induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA. ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke.