一般演題（口述）

一般演題（口述） Glia・Myelin（in Japanese）

3O2-01 Impaired late endosomal/lysosomal lipid trafficking attenuates oligodendrocyte differentiation and myelination in Niemann-Pick disease type C Kishi Soichiro¹，Kouchi Zen¹，Inamura Naoko¹，Chiba Yoichi²，Michikawa Makoto³，Takebayashi Hirohide⁴，Hosokawa Masanori¹，Enokido Yasushi¹ ¹Dept. of Pathol., Inst. of Dev. Res., Aichi Human Service Cntr，²Dept. of Pathol. and Host Defense, Faclt of Med., Kagawa Univ.，³Dept. of Biochem., Grad. Sch. of Med., Nagoya City Univ.，⁴Div. of Neurobiol. and Anat., Grad. Sch. of Med., Niigata Univ. Niemann-Pick disease type C（NPC）is a childhood-onset autosomal recessive disorder exhibiting progressive neurodegeneration and myelin defects caused by mutations in either the NPC1 or the NPC2 genes. These mutations affect the late endosomal/lysosomal（LE/Lys）lipid trafficking, resulting in the abnormal intracellular accumulation of unesterified cholesterol and glycosphingolipids；however, the underlying pathophysiology is still poorly understood. Here we examined impact of impaired LE/Lys lipid trafficking on the differentiation of oligodendrocyte（OL）, a myelin-forming cell which critically regulates CNS myelination, in vivo and in vitro. In the developing NPC1-deficient（NPC1-/-）mouse brain, extensive dysmyelination, and abnormal LE/Lys cholesterol accumulation in OLs and oligodendrocyte precursor cells（OPCs）were observed from early postnatal age, as well as in neurons. In primary cultures of OPCs, treatment of U18666A, a type-II amphiphile which causes intralysosomal accumulation of cholesterol by inhibiting LE/Lys lipid trafficking and NPC-like pathology, affected OL differentiation. Collectively, our results suggest that uptake and intercellular transport of cholesterol plays a critical role for OL differentiation and myelination in the CNS.		3O2-02 Prostaglandin F2α FP receptor inhibitor reduce demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model Yoshikawa Keisuke，Iwasa Kensuke，Yamamoto Shinji，Maruyama Kei，Takahashi Marika Dept. of Pharmacol., Faculty of Med., Saitama medical univ. Previously, we have demonstrated that prostamide/PGF synthase, catalyzes the reduction of prostaglandin（PG）H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, and glial activation in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.

3O2-03 2-Carba-cyclic phosphatidic acid, a chemically synthesized cyclic phosphatidic acid derivative, is a novel drug candidate for multiple sclerosis Yamamoto Shinji¹，Shimizu Yoshibumi²，Gotoh Mari²，Maruyama Kei¹，Murakami-Murofushi Kimiko²，Yoshikawa Keisuke¹ ¹Department of Pharmacology, Faculty of Medicine, Saitama Medical Univ，²Endowed Research Division of Human Welfare Sciences, Ochanomizu Univ Multiple sclerosis（MS）is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, and axonal pathology. The cuprizone model of demyelination is characterized by apoptotic death of mature oligodendrocytes, and is accompanied by neuroinflammation and motor dysfunction.Cyclic phosphatidic acid（cPA）has a unique structure consisting of a cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We previously reported that the administration of cPA reduced cuprizone-induced demyelination. In this study, we investigated the effects of 2ccPA, a chemically synthesized cPA derivative, on the cuprizone-induced demyelination. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, and motor dysfunction. Simultaneous administration of 2ccPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that 2ccPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. 2ccPA is a potential lead compound in the development of drugs for multiple sclerosis.