title: Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis.
abstract: Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.
authors.affiliation: Department of Neurology.
authors.forename: Spencer M
authors.identifier: http://orcid.org/0000-0001-9811-9007
authors.initials: SM
authors.lastname: Moore
authors.affiliation: Department of Neurology, Division of Biomedical Sciences at the School of Medicine, University of California, Riverside, CA 92521;
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Khalaj
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience at the School of Medicine, University of California, Los Angeles, CA 90095; and.
authors.forename: Shalini
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Neurology, Division of Biomedical Sciences at the School of Medicine, University of California, Riverside, CA 92521;
authors.forename: Zachary
authors.initials: Z
authors.lastname: Winchester
authors.affiliation: Department of Neurology.
authors.forename: JaeHee
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Neurology.
authors.forename: Timothy
authors.initials: T
authors.lastname: Yoo
authors.affiliation: Department of Neurology, Division of Biomedical Sciences at the School of Medicine, University of California, Riverside, CA 92521;
authors.forename: Leonardo
authors.initials: L
authors.lastname: Martinez-Torres
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Neurology, Division of Biomedical Sciences at the School of Medicine, University of California, Riverside, CA 92521; Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience at the School of Medicine, University of California, Los Angeles, CA 90095; and Brain Research Institute, and seema.tiwari-woodruff@ucr.edu.
authors.forename: Seema Kaushalya
authors.initials: SK
authors.lastname: Tiwari-Woodruff
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D047629:Estrogen Receptor beta / Q000819:agonists*; D005260:Female; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000494:pharmacology*; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects* / Q000502:physiology; D045442:Rotarod Performance Test
chemical_list: D047629:Estrogen Receptor beta; D006843:Hydrocarbons, Chlorinated; D007155:Immunologic Factors; D007191:Indazoles
keywords: PI3/Akt/mTOR; cuprizone diet; experimental autoimmune encephalomyelitis; motor deficit; remyelination