PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice

He Wu, Tao Wu, Wei Hua, Xianghui Dong, Yufeng Gao, Xiaochun Zhao, Wenwu Chen, Wangsen Cao, Qingwu Yang, Jiping Qi, Jin Zhou, Jian Wang

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1439-1450
Number of pages12
JournalNeurobiology of aging
Volume36
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • Glycyrrhizin
  • High-mobility group box 1
  • Inflammation
  • Matrix metalloproteinase
  • PGE
  • Src

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Aging
  • General Neuroscience
  • Developmental Biology

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