The PGE2 EP2 receptor and its selective activation are beneficial against ischemic stroke.
BACKGROUND
The prostaglandin E2 EP2 receptor has been shown to be important in dictating outcomes in various neuroinflammatory disorders. Here, we investigated the importance of the EP2 receptor in short- and long-term ischemic outcomes by subjecting wildtype (WT) and EP2 knockout (EP2-/-) mice to two distinct and complementary stroke models [transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO)] and by using the EP2 receptor agonist ONO-AE1-259-01.


METHODS
First, WT and EP2-/- mice were subjected to 90-min tMCAO with a monofilament followed by 4-day reperfusion. Second, WT mice were infused intracerebroventricularly with vehicle or ONO-AE1-259-01 45-50 min before being subjected to tMCAO. Finally, WT and EP2-/- mice were subjected to pMCAO and allowed to survive for an extended period of 7 days.


RESULTS
Infarct volumes in EP2-/- mice were 55.0 +/- 9.1% larger after tMCAO and 33.3 +/- 8.6% larger after pMCAO than those in WT mice. Neurobehavioral deficits also were significantly greater in the EP2-/- mice. These results suggest that EP2 is beneficial and that activation is sustained for days after the stroke. We also found that pharmacologic activation of EP2 with 1.0- and 2.0-nmol doses of ONO-AE1-259-01 was sufficient to significantly reduce the infarct volume in WT mice compared with that in vehicle-treated controls (20.1 +/- 3.9% vs. 37.1 +/- 4.6%). This reduction correlated with improved neurologic scores. No significant effect on physiologic parameters was observed.


CONCLUSIONS
Together, our results reveal that pharmacologic stimulation of the EP2 receptor has an important beneficial role in cerebral ischemia and might be considered as an adjunct therapy for ischemic stroke.
Ahmad
Muzamil
M
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
Saleem
Sofiyan
S
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
Shah
Zahoor
Z
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
Maruyama
Takayuki
T
Pharmacological Research Laboratories, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, Japan.
Narumiya
Shuh
S
Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
Doré
Sylvain
S
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, 21205, USA.