title: Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination.
abstract: Differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes is a prerequisite for remyelination after demyelination, and impairment of this process is suggested to be a major reason for remyelination failure. Diosgenin, a plant-derived steroid, has been implicated for therapeutic use in many diseases, but little is known about its effect on the central nervous system. In this study, using a purified rat OPC culture model, we show that diosgenin significantly and specifically promotes OPC differentiation without affecting the viability, proliferation, or migration of OPC. Interestingly, the effect of diosgenin can be blocked by estrogen receptor (ER) antagonist ICI 182780 but not by glucocorticoid and progesterone receptor antagonist RU38486, nor by mineralocorticoid receptor antagonist spirolactone. Moreover, it is revealed that both ER-alpha and ER-beta are expressed in OPC, and diosgenin can activate the extracellular signal-regulated kinase 1/2 (ERK1/2) in OPC via ER. The pro-differentiation effect of diosgenin can also be obstructed by the ERK inhibitor PD98059. Furthermore, in the cuprizone-induced demyelination model, it is demonstrated that diosgenin administration significantly accelerates/enhances remyelination as detected by Luxol fast blue stain, MBP immunohistochemistry and real time RT-PCR. Diosgenin also increases the number of mature oligodendrocytes in the corpus callosum while it does not affect the number of OPCs. Taking together, our results suggest that diosgenin promotes the differentiation of OPC into mature oligodendrocyte through an ER-mediated ERK1/2 activation pathway to accelerate remyelination, which implicates a novel therapeutic usage of this steroidal natural product in demyelinating diseases such as multiple sclerosis (MS).
authors.affiliation: Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of Ministry of Education, Neuroscience Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xiao
authors.forename: Dazhi
authors.initials: D
authors.lastname: Guo
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
authors.forename: Weiran
authors.initials: W
authors.lastname: Shen
authors.forename: Lei
authors.initials: L
authors.lastname: Shan
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Liu
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004144:Diosgenin / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004144:Diosgenin