title: HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.
abstract: Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 μM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH.
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, Japan. ohnishi@fupharm.fukuyama-u.ac.jp
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Chiharu
authors.initials: C
authors.lastname: Fukutomi
authors.forename: Madoka
authors.initials: M
authors.lastname: Takahashi
authors.forename: Misato
authors.initials: M
authors.lastname: Motomura
authors.forename: Mizuki
authors.initials: M
authors.lastname: Fukunaga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Isohama
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Atsuko
authors.initials: A
authors.lastname: Inoue
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D017364:Collagenases / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D019695:Glycyrrhizic Acid / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D006490:Hemostatics / Q000494:pharmacology; D008297:Male; D058990:Molecular Targeted Therapy; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013917:Thrombin / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; D006490:Hemostatics; D009569:Nitric Oxide; D019695:Glycyrrhizic Acid; D013917:Thrombin; D017364:Collagenases