title: Glycyrrhizin protects brain against ischemia-reperfusion injury in mice through HMGB1-TLR4-IL-17A signaling pathway.
abstract: High mobility group box 1 (HMGB1)-Toll-like receptor 4 (TLR4) signaling has been recently found to induce interleukin (IL)-17A secretion in drug-induced hepatitis and myocardial I/R injury. The purpose of this study is to evaluate whether HMGB1-TLR4 signaling could induce IL-17A secretion and lead to brain I/R injury. We also sought to investigate whether glycyrrhizin elucidated its neuroprotective effects through HMGB1-TLR4-IL-17A signaling pathway. Various biochemical estimations, neurological status, and assessment of cerebral infarct size were carried out 72h after middle cerebral artery occlusion (MCAO) stroke. Apoptotic cells were assessed using a terminal deoxynucleotidyl transferase, dUTP nick and labeling (TUNEL) kit. The expression of HMGB1, IL-17A, bcl-2, bax and cleaved caspase-3, were determined by Western blot assay. In the present study we found that glycyrrhizin significantly decreased HMGB1 protein expression. Glycyrrhizin markedly reduced whereas recombinant HMGB1 (rHMGB1) increased IL-17A expression. HMGB1 induced increase of IL-17A was significantly diminished in TLR4-mutant C3H/HeJ mice. Brain injury and neurological deficits were largely abrogated by glycyrrhizin or IL-17A knockout. In contrast, rHMGB1 or recombinant mouse IL-17A markedly increased I/R injury. However, rHMGB1 had no effects on infarct size and neurological deficits in Il17a(-/-) mice following brain I/R injury. In addition, IL-17A knockout mice significantly increased bcl-2 protein expression and had fewer apoptotic cells, whereas recombinant IL-17A-treated mice significantly increased bax and cleaved caspase-3 protein expression and had more apoptotic cells. Together these results indicate that glycyrrhizin has neuroprotective efficacy in the postischemic brain through HMGB1-TLR4-IL-17A signaling pathway.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Zelin
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: franklinyun@hust.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D018696:Neuroprotective Agents; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019695:Glycyrrhizic Acid
keywords: Apoptosis; Cerebral ischemia; Glycyrrhizin; HMGB1; IL-17A; MCAO; TLR4