title: Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model.
abstract: Previously, we have demonstrated that prostamide/PGF synthase, which 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, glial activation, and TNFα expression 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iwasa
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Awaji
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. Electronic address: keisukey@saitama-med.ac.jp.
authors.forename: K
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D015237:Dinoprost / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D044262:Prostaglandin H2 / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; C034671:prostaglandin F2alpha receptor; C121227:AL 8810; D044262:Prostaglandin H2; D003471:Cuprizone; D015237:Dinoprost
keywords: Cuprizone (CPZ); Demyelination; Multiple sclerosis (MS); Neuroinflammation; Prostaglandin F(2α) receptor (FP)