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Role of PGE2 EP1 Receptor in Intracerebral Hemorrhage-Induced Brain Injury

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Abstract

Prostaglandin E2 (PGE2) has been described to exert beneficial and detrimental effects in various neurologic disorders. These conflicting roles of PGE2 could be attributed to its diverse receptor subtypes, EP1–EP4. At present, the precise role of EP1 in intracerebral hemorrhage (ICH) is unknown. Therefore, to elucidate its possible role in ICH, intrastriatal injection of collagenase was given in randomized groups of adult male wildtype (WT) and EP1 receptor knockout (EP1−/−) C57BL/6 mice. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 24, 48, and 72 h post-ICH. Lesion volume, cell survival and death, were assessed using Cresyl Violet, and Fluoro-Jade staining, respectively. Microglial activation and phagocytosis were estimated using Iba1 immunoreactivity and fluorescently-labeled microspheres. Following 72 h post-ICH, EP1−/− mice showed deteriorated outcomes compared to the WT control mice. These outcomes were demonstrated by elevated neurological deficits, exacerbated lesion volume, and significantly worsened sensorimotor functions. Fluoro-Jade staining showed significantly increased numbers of degenerating neurons and reduced neuronal survival in EP1−/− compared to WT mice. To assess in vivo phagocytosis, the number of microspheres phagocytosed by Iba1-positive cells was 145.4 ± 15.4 % greater in WT compared to EP1−/− mice. These data demonstrate that EP1 deletion exacerbates neuro-behavioral impairments following ICH, potentially by slowing down/impairing microglial phagocytosis. A better understanding of this EP1 mechanism could lead to improved intervention strategies for hemorrhagic stroke.

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Acknowledgements and Financial support

We thank all Doré lab team members for their active participation. National Institutes of Health (NS046400, AG022971) to SD, and the American Heart Association (09POST2080364) to BM.

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Authors and Affiliations

  1. Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, Biomed Sci J493, PO Box 100159, Gainesville, FL, 32610-0159, USA

    Nilendra Singh, Christopher Charles Leonardo, Abdullah Shafique Ahmad & Sylvain Doré

  2. Division of Neurogenetics, National Institute on Aging, Bethesda, MD, 21225, USA

    Bo Ma

  3. Department of Pharmacology, Kyoto University, Kyoto, 606-8315, Japan

    Shuh Narumiya

  4. Departments of Neuroscience, Neurology, and Psychiatry, University of Florida, Gainesville, FL, 32610, USA

    Sylvain Doré

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  1. Nilendra Singh
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  2. Bo Ma
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  3. Christopher Charles Leonardo
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  4. Abdullah Shafique Ahmad
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  5. Shuh Narumiya
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  6. Sylvain Doré
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Correspondence to Sylvain Doré.

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Nilendra Singh and Bo Ma contributed equally to this study.

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Singh, N., Ma, B., Leonardo, C.C. et al. Role of PGE2 EP1 Receptor in Intracerebral Hemorrhage-Induced Brain Injury. Neurotox Res 24, 549–559 (2013). https://doi.org/10.1007/s12640-013-9410-7

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  • DOI: https://doi.org/10.1007/s12640-013-9410-7

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