Although some of the COX-2 metabolites and
prostaglandins have been implicated in
stroke and excitotoxicity, the role of
prostaglandin F(2alpha) (
PGF(2alpha)) 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
PGF(2alpha)
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.