Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice

Xiaochun Zhao, Tao Wu, Che Feng Chang, He Wu, Xiaoning Han, Qian Li, Yufeng Gao, Qiang Li, Zhipeng Hou, Takayuki Maruyama, Jiangyang Zhang, Jian Wang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)293-310
Number of pages18
JournalBrain, Behavior, and Immunity
Volume46
DOIs
StatePublished - May 1 2015

Fingerprint

Prostaglandin Receptors
Poisons
Cerebral Hemorrhage
Dinoprostone
Collagenases
Brain Injuries
src-Family Kinases
Matrix Metalloproteinase 9
Thrombin
Magnetic Resonance Imaging
Brain Edema
Microglia
Astrocytes
Prostaglandins
Atrophy
Fluorescent Antibody Technique
Axons
Oxidative Stress
Cell Death
Phosphorylation

Keywords

  • Diffusion tensor imaging
  • Hemoglobin
  • Inflammation
  • Intracerebral hemorrhage
  • Magnetic resonance imaging
  • Matrix metalloproteinase
  • Prostaglandin EP1 receptor
  • Src-kinase

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems

Cite this

Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. / Zhao, Xiaochun; Wu, Tao; Chang, Che Feng; Wu, He; Han, Xiaoning; Li, Qian; Gao, Yufeng; Li, Qiang; Hou, Zhipeng; Maruyama, Takayuki; Zhang, Jiangyang; Wang, Jian.

In: Brain, Behavior, and Immunity, Vol. 46, 01.05.2015, p. 293-310.

Research output: Contribution to journalArticle

Zhao, X, Wu, T, Chang, CF, Wu, H, Han, X, Li, Q, Gao, Y, Li, Q, Hou, Z, Maruyama, T, Zhang, J & Wang, J 2015, 'Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice', Brain, Behavior, and Immunity, vol. 46, pp. 293-310. https://doi.org/10.1016/j.bbi.2015.02.011
Zhao, Xiaochun ; Wu, Tao ; Chang, Che Feng ; Wu, He ; Han, Xiaoning ; Li, Qian ; Gao, Yufeng ; Li, Qiang ; Hou, Zhipeng ; Maruyama, Takayuki ; Zhang, Jiangyang ; Wang, Jian. / Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. In: Brain, Behavior, and Immunity. 2015 ; Vol. 46. pp. 293-310.
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