Abstract
BackgroundThe 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.MethodsFirst, 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.ResultsInfarct 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.ConclusionTogether, 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.
Highlights
Prostaglandin E2 (PGE2), formed from arachidonic acid by the action of cyclooxygenases and PGE2 synthases, was previously considered to be a pro-inflammatory prostaglandin, but it may have a much more complex role
The relative cerebral blood flow (CBF) dropped more than 80% from baseline after transient middle cerebral artery occlusion (tMCAO) and returned to near baseline after reperfusion in WT and EP2-/- mice (Figure 2)
Using EP2-/- mice, we showed that the EP2 receptor is protective in cortical and striatal brain regions affected by tMCAO and in the cortex after permanent middle cerebral artery occlusion (pMCAO) but that its deletion does not affect the gross cerebrovascular anatomy or the physiologic parameters of blood pH, PaO2, PaCO2, or mean arterial blood pressure (MABP)
Summary
Prostaglandin E2 (PGE2), formed from arachidonic acid by the action of cyclooxygenases and PGE2 synthases, was previously considered to be a pro-inflammatory prostaglandin, but it may have a much more complex role. PGE2 executes its functions by binding mainly to four membrane-bound G-protein-coupled receptors known as Eprostanoid (EP) 1, 2, 3, and 4 These EP receptors have varied effects on cyclic adenosine monophosphate (cAMP) production, phosphoinositol turnover, and intracellular calcium level regulation [1]. The EP2 receptor has been reported to be highly expressed in cerebral cortex, striatum, and hippocampus [7,8] Genetic knockout of this receptor significantly increases lesion volume at the 24-h time point in mice subjected to ischemic paradigms, with no apparent change in behavior [9,10]. 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
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