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PO2-1-35

mPGES-1 inhibitor ameliorates ischemic brain injury by suppression of neuronal / microglial PGE2 production and inflammation

[Speaker] Yuri Ikeda-Matsuo:1,2
[Co-author] Ayako Ouchi:2, Mika Shikuri:2, Yasuhito Naito:2, Takashi Iwai:2, Syun Watanabe:2, Misa Oyama:2, Per-Johan Jakobsson:3, Mitsuo Tanabe:2
1:Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan, 2:Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Kitasato University, Japan, 3:Department of Medicine, Karolinska Institute, Sweden

We previously demonstrated that induction of microsomal prostaglandin E synthase-1 (mPGES-1) contributes to the exaggeration of stroke injury by using mPGES-1 knockout (KO) mice and a recently discovered murine mPGES-1 inhibitor, 1-(1-Isopropyl-5,6-dimethyl-1H-benzoimidazol-2-yl)-piperidine- 4-carboxylic acid cyclopentylamide (C-III). In this study, we examined the mechanisms of protective effect of C-III on stroke injury. We injected C-III (50 mg/kg, i.p.) after reperfusion of middle cerebral artery occlusion for 1.5 h. The ischemia-induced infarction, edema and neurological deficits were significantly improved by injection of C-III. The production of PGE2, but not PGI2 and TXA2, in striatum after ischemia is significantly reduced by C-III. Although PGE2 is known to affect body temperature and vasoconstriction, C-III did not affect rectal temperature, blood pressure, heart rate and the cerebral blood flow after ischemia. We next examined the effect of C-III on brain inflammation and neuronal apoptosis. The mRNA inductions of TNF-α, IL-1β and IL-6 were significantly reduced by C-III. Activation of caspase-3 observed in cortex and striatum was also significantly inhibited by C-III. Because PGE2 is known to accelerate inflammation by feedback activation of PGE2 signal, we examined the effect of C-III on PGE2 synthases and EP receptors. The induction of mPGES-1 and COX-2 mRNA was significantly inhibited by C-III, while the constitutive expressions of EP receptors were not significantly affected. In cultured mouse hippocampal slices, the glutamate-induced excitotoxicity in CA1 neurons were inhibited by C-III in WT slices, but not in mPGES-1KO slices, in which excitotoxicity was less as compared with WT mice slices. Furthermore, in cultured rat cortical neurons, glutamate-induced excitotoxicity and PGE2 production were also inhibited by C-III. The excitotoxicity was not significantly affected by co-culture with astrocytes, while surviving neurons were significantly decreased by co-culture with microglia even without glutamate exposure. The neurotoxicity induced by co-culturing microglia was significantly inhibited by C-III. These results suggest that Inhibition of neuronal and microglial PGE2 production by mPGES-1 inhibitor ameliorates ischemic brain injury through inhibition of inflammatory reactions and apoptosis. Thus, treatment of mPGES-1 inhibitor after onset of brain ischemia will be the novel therapeutic strategy for human stroke.
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