title: G protein-coupled receptor 30 contributes to improved remyelination after cuprizone-induced demyelination.
abstract: Estrogen exerts neuroprotective and promyelinating actions. The therapeutic effect has been shown in animal models of multiple sclerosis, in which the myelin sheath is specifically destroyed in the central nervous system. However, it remains unproven whether estrogen is directly involved in remyelination via the myelin producing cells, oligodendrocytes, or which estrogen receptors are involved. In this study, we found that the membrane-associated estrogen receptor, the G protein-coupled receptor 30 (GPR30), also known as GPER, was expressed in oligodendrocytes in rat spinal cord and corpus callosum. Moreover, GPR30 was expressed throughout oligodendrocyte differentiation and promyelinating stages in primary oligodendrocyte cultures derived from rat spinal cords and brains. To evaluate the role of signaling via GPR30 in promyelination, a specific agonist for GPR30, G1, was administered to a rat model of demyelination induced by cuprizone treatment. Histological examination of the corpus callosum with oligodendrocyte differentiation stage-specific markers showed that G1 enhanced oligodendrocyte maturation in corpus callosum of cuprizone-treated animals. It also enhanced oligodendrocyte ensheathment of dorsal root ganglion (DRG) neurons in co-culture and myelination in cuprizone-treated animals. This study is the first evidence that GPR30 signaling promotes remyelination by oligodendrocytes after demyelination. GPR30 ligands may provide a novel therapy for the treatment of multiple sclerosis.
authors.affiliation: Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Japan. hirahary@takii.kmu.ac.jp
authors.forename: Yukie
authors.initials: Y
authors.lastname: Hirahara
authors.forename: Ken Ichi
authors.initials: KI
authors.lastname: Matsuda
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamada
authors.forename: Akira
authors.initials: A
authors.lastname: Saitou
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Morisaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Takanami
authors.forename: Joan M
authors.initials: JM
authors.lastname: Boggs
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawata
mesh_terms: D000818:Animals; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C520305:Gper1 protein, rat; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators; D003471:Cuprizone