1-P-051
クプリゾン誘発脱髄および運動機能障害における膜型プロスタグランジンE合成酵素-1の役割
Role of the microsomal prostaglandin E synthase-1 in cuprizone-induced demyelination and motor dysfunction.
〇小島 史章1,2、関谷 広樹1,2、川田 逸人3、柏木 仁4、今道 力敬4、結城 幸一4、牛首 文隆4、北里 英郎3、市川 尊文2
Fumiaki Kojima1,2, Hiroki Sekiya1,2, Hayato Kawada3, Hitoshi Kashiwagi4, Yoshitaka Imamichi4, Koh-Ichi Yuhki4, Fumitaka Ushikubi4, Hidero Kitasato3, Takafumi Ichikawa2
1北里大・医療衛生・薬理、2北里大・院医療・生体制御生化、3北里大・院医療・環境微生物、4旭川医科大・医・薬理
1Department of Pharmacology, Kitasato University, 2Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 3Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 4Department of Pharmacology, Asahikawa Medical University
Multiple sclerosis (MS) is one of the most common demyelinating diseases. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation and immune responses by converting prostaglandin (PG) H2 to PGE2. PGE2 is highly produced in the cerebrospinal fluid of patients with MS. However, the role of mPGES-1 in MS has not been fully elucidated yet. In this study, we demonstrate the role of mPGES-1 in demyelination and motor dysfunction induced by cuprizone, one of the well established models of MS. Demyelination in the brain was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by feeding ad libitum with a powdered diet containing 0.2% cuprizone for 6 weeks under specific pathogen free condition. The expression of mPGES-1 in the brain was determined by real-time PCR. The cuprizone-induced demyelination was assessed by a myelin staining with coronal brain sections, and motor dysfunction was evaluated by the rotarod test. Cuprizone up-regulated the expression of mPGES-1 mRNA in the brain of WT mice. Interestingly, mPGES-1−/− mice exhibited lower degree of demyelination compared to WT mice. In addition, mPGES-1 gene deletion or COX-2 selective inhibitor celecoxib reduced cuprizone-induced motor dysfunction. These data indicate that COX-2/mPGES-1/PGE2 system contributes to the pathophysiology of MS and open possible novel therapeutic approaches for MS.