Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury.
Although augmented prostaglandin E(2) (PGE(2)) synthesis and accumulation have been demonstrated in the lesion sites of rodent transient focal ischemia models, the role of PGE(2) in neuronal survival has been controversial, showing both protective and toxic effects. Here we demonstrate the induction of microsomal PGE synthase 1 (mPGES-1), an inducible terminal enzyme for PGE(2) synthesis, in neurons, microglia, and endothelial cells in the cerebral cortex after transient focal ischemia. In mPGES-1 knockout (KO) mice, in which the postischemic PGE(2) production in the cortex was completely absent, the infarction, edema, apoptotic cell death, and caspase-3 activation in the cortex after ischemia were all reduced compared with those in wild-type (WT) mice. Furthermore, the behavioral neurological dysfunctions observed after ischemia in WT mice were significantly ameliorated in KO mice. The ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as WT mice by intracerebroventricular injection of PGE(2) into KO mice. Our observations suggest that mPGES-1 may be a critical determinant of postischemic neurological dysfunctions and a valuable therapeutic target for treatment of human stroke.
Ikeda-Matsuo
Yuri
Y
Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan. matsuoy@pharm.kitasato-u.ac.jp
Ota
Azusa
A
Fukada
Tetsuya
T
Uematsu
Satoshi
S
Akira
Shizuo
S
Sasaki
Yasuharu
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D020521:Stroke / Q000378:metabolism / Q000473:pathology
D007527:Isoenzymes; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone