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PGF2α FP Receptor Contributes to Brain Damage Following Transient Focal Brain Ischemia

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Abstract

Although some of the COX-2 metabolites and prostaglandins have been implicated in stroke and excitotoxicity, the role of prostaglandin F2α (PGF2α) and its FP receptor have not been elucidated in the pathogenesis of ischemic-reperfusion (I/R) brain injury. Here we investigated the FP receptor’s contribution in a unilateral middle cerebral artery (MCA) occlusion model of focal cerebral ischemia in mice. The MCA in wild type (WT) and FP knockout (FP−/−) C57BL/6 male mice was transiently occluded with a monofilament for 90 min. After 96 h of reperfusion, the FP−/− mice had 25.3% less neurological deficit (P < 0.05) and 34.4% smaller infarct volumes (P < 0.05) than those of the WT mice. In a separate cohort, physiological parameters were monitored before, during, and after ischemia, and the results revealed no differences between the groups. Because excitotoxicity is an acute mediator of stroke outcome, the effect of acute NMDA-induced neurotoxicity was also tested. Forty-eight hours after unilateral intrastriatal NMDA injection, excitotoxic brain damage was 20.8% less extensive in the FP−/− mice (P < 0.05) than in the WT counterparts, further supporting the toxic contribution of the FP receptor in I/R injury. Additionally, we investigated the effect of post-treatment with the FP agonist latanoprost in mice subjected to MCA occlusion; such treatment resulted in an increase in neurological deficit and infarct size in WT mice (P < 0.05), though no effects were observed in the latanoprost-treated FP−/− mice. Together, the results suggest that the PGF2α FP receptor significantly enhances cerebral ischemic and excitotoxic brain injury and that these results are of importance when planning for potential development of therapeutic drugs to treat stroke and its acute and/or long term consequences.

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Abbreviations

CBF:

Cerebral blood flow

COX:

Cyclooxygenase

DMSO:

Dimethyl sulfoxide

I/R:

Ischemia-reperfusion

MABP:

Mean arterial blood pressure

MCA:

Middle cerebral artery

MCAO:

Middle cerebral artery occlusion

PG:

Prostaglandin

WT:

Wild type

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Acknowledgments

This work was supported in part by grants from the National Institutes of Health NS046400 and AG022971 (SD). We thank all members of the Doré lab team for assistance in this project, and Claire Levine for assistance in the preparation of the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 365, Baltimore, MD, 21205, USA

    Sofiyan Saleem, Abdullah Shafique Ahmad & Sylvain Doré

  2. Pharmacological Research Laboratories, Ono Pharmaceutical Co. Ltd, Mishima-gun, Osaka, Japan

    Takayuki Maruyama

  3. Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, 606-8501, Japan

    Shuh Narumiya

Authors
  1. Sofiyan Saleem
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  2. Abdullah Shafique Ahmad
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  3. Takayuki Maruyama
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  4. Shuh Narumiya
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  5. Sylvain Doré
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Correspondence to Sylvain Doré.

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Sofiyan Saleem and Abdullah Shafique Ahmad contributed equally to this work.

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Saleem, S., Ahmad, A.S., Maruyama, T. et al. PGF2α FP Receptor Contributes to Brain Damage Following Transient Focal Brain Ischemia. Neurotox Res 15, 62–70 (2009). https://doi.org/10.1007/s12640-009-9007-3

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  • DOI: https://doi.org/10.1007/s12640-009-9007-3

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