Microsomal prostaglandin E synthase‐1 and cyclooxygenase‐2 are both required for ischaemic excitotoxicity

Background and purpose:  Although both microsomal prostaglandin E synthase (mPGES)‐1 and cyclooxygenase (COX)‐2 are critical factors in stroke injury, but the interactions between these enzymes in the ischaemic brain is still obscure. This study examines the hypothesis that mPGES‐1 activity is required for COX‐2 to cause neuronal damage in ischaemic injury.Experimental approach:  We used a glutamate‐induced excitotoxicity model in cultures of rat or mouse hippocampal slices and a mouse middle cerebral artery occlusion‐reperfusion model in vivo. The effect of a COX‐2 inhibitor on neuronal damage in mPGES‐1 knockout (KO) mice was compared with that in wild‐type (WT) mice.Key results:  In rat hippocampal slices, glutamate‐induced excitotoxicity, as well as prostaglandin (PG) E2 production and PGES activation, was significantly attenuated by either MK‐886 or NS‐398, inhibitors of mPGES‐1 and COX‐2 respectively; however, co‐application of these inhibitors had neither an additive nor a synergistic effect. The protective effect of NS‐398 on the excitotoxicity observed in WT slices was completely abolished in mPGES‐1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischaemia model, mPGES‐1 and COX‐2 were co‐localized in the infarct region of the cortex. Injection of NS‐398 reduced not only ischaemic PGE2 production, but also ischaemic injuries in WT mice, but not in mPGES‐1 KO mice, which showed less dysfunction than WT mice.Conclusion and implications:  Microsomal prostaglandin E synthase‐1 and COX‐2 are co‐induced by excess glutamate in ischaemic brain. These enzymes are co‐localized and act together to exacerbate stroke injury, by excessive PGE2 production.