Isorhynchophylline Relieves Ferroptosis-Induced Nerve Damage after Intracerebral Hemorrhage Via miR-122-5p/TP53/SLC7A11 Pathway

• Published in: Neurochemical research 2021-08, Vol.46 (8), p.1981-1994
• Main Authors: Zhao, Haikang, Li, Xiaoqiang, Yang, Lei, Zhang, Liang, Jiang, Xiaobing, Gao, Wenwen, Chen, Peng, Cheng, Yingying, Wang, Fenglu, Liu, Jianrong
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System y+ - metabolism; Ammonium; Animals; Antioxidants; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Line; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Citric acid; Damage; Ferric Compounds - toxicity; Ferroptosis; Ferroptosis - drug effects; Gene expression; Hemorrhage; Herbal medicine; Hippocampus; Inhibitors; Ion concentration; Iron; Lipids; Male; Markers; Mice; MicroRNAs - metabolism; Moisture content; Neurochemistry; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Original Paper; Oxidative stress; Oxindoles - pharmacology; Oxindoles - therapeutic use; p53 Protein; Proteins; Quaternary Ammonium Compounds - toxicity; Rats; Rats, Sprague-Dawley; siRNA; Stress concentration; Transfection; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; Water content
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-021-03320-2

Isorhynchophylline (IRN), a component of traditional Chinese herb Uncaria rhynchophylla , possesses strong antioxidant activity. Ferroptosis induced by iron overload causes cell oxidative stress after intracerebral hemorrhage (ICH). Therefore, this study aims to explore the effects of IRN on the ferroptosis following ICH. In this study, mouse hippocampal HT-22 cells were treated with ferric ammonium citrate (FAC) alone or together with IRN, and we found IRN reduced the FAC-induced cell damage. Then, cells were treated with IRN following treatment with FAC after transfection with miR-122-5p inhibitor, and the results showed IRN reduced the FAC-induced decrease of miR-122-5p levels and relieved the ferroptosis by detecting ferroptotic marker proteins, iron ion concentration and oxidative stress level; after transfection with miR-122-5p inhibitor, the protective effects of IRN against FAC-induced ferroptosis in these cells were weakened. TP53 (also known as p53) was verified as a target of miR-122-5p by using dual luciferase reporter assay, and restoration of TP53 attenuated the effects of miR-122-5p on ferroptotic marker proteins expression, iron ion concentration and lipid ROS levels, as well as solute carrier family seven member 11 (SLC7A11) mRNA expression. SLC7A11 siRNA reversed the inhibitory effects of IRN on FAC-induced ferroptosis and oxidative stress levels. Subsequently, IRN increased the mNSS score, and decreased brain water content and EB content in ICH model. Moreover, IRN decreased ferroptosis and lipid ROS level, upregulated the expression of miR-122-5p and SLC7A11 mRNA, and inhibited TP53 expression. Our findings reveal that IRN protects neurocyte from ICH-induced ferroptosis via miR-122-5p/TP53/SLC7A11 pathway, which may provide a potential therapeutic mechanism for ICH.