title: Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice.
abstract: Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Stroke Center, Stroke Screening and Intervention Base, Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: twu163@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Che-Feng
authors.initials: CF
authors.lastname: Chang
authors.affiliation: Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: He
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Project Management, Discovery and Research, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010077:Oxazepines / Q000494:pharmacology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D006834:Hydrazines; C500045:ONO-DI-004; D010077:Oxazepines; D058306:Receptors, Prostaglandin E, EP1 Subtype; C086836:SC 51089; D000527:Alprostadil
keywords: Diffusion tensor imaging; Hemoglobin; Inflammation; Intracerebral hemorrhage; Magnetic resonance imaging; Matrix metalloproteinase; Prostaglandin EP1 receptor; Src-kinase