title: PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice.
abstract: Intracerebral hemorrhage (ICH) is a devastating form of stroke. Misoprostol, a synthetic prostaglandin E1 (PGE1) analog and PGE2 receptor agonist, has shown protection against cerebral ischemia. In this study, we tested the efficacy of misoprostol in the 12-month-old mice subjected to 1 of 2 complementary ICH models, the collagenase model (primary study) and blood model (secondary study, performed in an independent laboratory). We also investigated its potential mechanism of action. Misoprostol posttreatment decreased brain lesion volume, edema, and brain atrophy and improved long-term functional outcomes. In the collagenase-induced ICH model, misoprostol decreased cellular inflammatory response; attenuated oxidative brain damage and gelatinolytic activity; and decreased high-mobility group box 1 (HMGB1) expression, Src kinase activity, and interleukin-1β expression without affecting cyclooxygenase-2 expression. Furthermore, HMGB1 inhibition with glycyrrhizin decreased Src kinase activity, gelatinolytic activity, neuronal death, and brain lesion volume. Src kinase inhibition with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) decreased gelatinolytic activity and brain edema and improved neurologic function but did not decrease HMGB1 protein level. These results indicate that misoprostol protects brain against ICH injury through mechanisms that may involve the HMGB1, Src kinase, and matrix metalloproteinase-2/9 pathways.
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: He
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA; Stroke Center, Stroke Screening and Intervention Base, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Basic Medical Science, Nanjing University School of Medicine, Nanning, China.
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China. Electronic address: qijiping2003@163.com.
authors.forename: Jiping
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Hematology, First Clinical Hospital, Harbin Medical University, Harbin, China. Electronic address: zhoujin1960@hotmail.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D007249:Inflammation; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016595:Misoprostol / Q000494:pharmacology* / Q000627:therapeutic use*; D018696:Neuroprotective Agents; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D018078:Receptors, Prostaglandin E; D016595:Misoprostol; D016220:Fibroblast Growth Factor 1; D019695:Glycyrrhizic Acid; D019061:src-Family Kinases; D020778:Matrix Metalloproteinase 2
keywords: Glycyrrhizin; High-mobility group box 1; Inflammation; Matrix metalloproteinase; PGE(2); Src