title: [The role of prostaglandin E2 in stroke-reperfusion injury].
abstract: Although augmented prostaglandin E2 (PGE2) accumulation has been demonstrated at the lesion sites of rodent ischemia models, the role of postischemic PGE2 in neuronal survival has remained obscure. We recently identified the microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for prostaglandin E2 synthesis, as a critical factor in stroke-reperfusion injury. Co-induction of mPGES-1 and cyclooxygenase (COX)-2, an upstream enzyme for PGE2 production, was observed after brain ischemia. In mPGES-1 knockout (KO) mice, in which the postischemic PGE2 production in the cortex was completely absent, the ischemic injuries were less severe compared to those in wild-type (WT) mice. The ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as in the WT mice by intracerebroventricular injection of PGE2 into KO mice. The induction of mPGES-1 was also observed after glutamate exposure in cultured hippocampal slices. In mPGES-1 KO slices, glutamate-induced excitotoxicity was less severe compared to that in WT slices. Among the EP1-4 antagonists and agonists, only the EP3 antagonist attenuated and only the EP3 agonist augmented the glutamate-induced excitotoxicity. Furthermore, intraperitoneal injection of COX-2 inhibitor or EP3 antagonist reduced the ischemic injuries in WT mice, but not in mPGES-1 KO mice. In EP3 KO mice, the ischemic injuries were less severe compared to those in WT mice. These results suggest that mPGES-1 and COX-2 are co-induced by excessive glutamate in the ischemic brain and act together to exacerbate stroke injury through PGE2 production followed by activation of EP3 receptors.
authors.affiliation: Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan. matsuoy@pharm.kitasato-u.ac.jp
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ikeda-Matsuo
mesh_terms: D051546:Cyclooxygenase 2 / Q000502:physiology; D015232:Dinoprostone / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D015427:Reperfusion Injury / Q000378:metabolism*; D020521:Stroke / Q000378:metabolism*
chemical_list: C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone