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The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic.

ABSTRACT: We investigated the preclinical characteristics of the neuroprotective effect of the prostaglandin E2 type 1 receptor (EP1) antagonist SC51089 in models of focal cerebral ischemia produced by occlusion of the mouse middle cerebral artery (MCA). We found that systemic administration of SC51089 (5 to 20 microg/kg; i.p.) reduces the brain injury produced by transient (-50%+/-8%; n=12; P<0.05) or permanent (-39%+/-7%; n=12; P<0.05) MCA occlusion. SC51089 was effective even when administered up to 12 h after ischemia. The protective effect was observed both in male and female mice and was sustained for at least 2 weeks after induction of ischemia. The reduction in injury volume was associated with an improvement in neurological function assessed by the Bederson deficit score, the hanging wire test and the corner test. The data provide proof of principle that EP1 receptor inhibition is a potentially valuable strategy for neuroprotection that deserves further preclinical investigation for therapeutic application in human stroke.

SUBMITTER: Abe T

PROVIDER: S-EPMC2748840 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic.

Abe Takato T Kunz Alexander A Shimamura Munehisa M Zhou Ping P Anrather Josef J Iadecola Costantino C

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20080723 1

We investigated the preclinical characteristics of the neuroprotective effect of the prostaglandin E2 type 1 receptor (EP1) antagonist SC51089 in models of focal cerebral ischemia produced by occlusion of the mouse middle cerebral artery (MCA). We found that systemic administration of SC51089 (5 to 20 microg/kg; i.p.) reduces the brain injury produced by transient (-50%+/-8%; n=12; P<0.05) or permanent (-39%+/-7%; n=12; P<0.05) MCA occlusion. SC51089 was effective even when administered up to 12 ...[more]

PMID: 18648380

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Project description: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.

Dataset Information

The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic.

Publications

The neuroprotective effect of prostaglandin E2 EP1 receptor inhibition has a wide therapeutic window, is sustained in time and is not sexually dimorphic.

Similar Datasets

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