title: Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects.
abstract: Demyelination in multiple sclerosis (MS) leads to significant, progressive axonal and neuronal degeneration. Currently existing immunosuppressive and immunomodulatory therapies alleviate MS symptoms and slow, but fail to prevent or reverse, disease progression. Restoration of damaged myelin sheath by replenishment of mature oligodendrocytes (OLs) should not only restore saltatory axon conduction, but also provide a major boost to axon survival. Our previous work has shown that therapeutic treatment with the modestly selective generic estrogen receptor (ER) β agonist diarylpropionitrile (DPN) confers functional neuroprotection in a chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS by stimulating endogenous remyelination. Recently, we found that the more potent, selective ERβ agonist indazole-chloride (Ind-Cl) improves clinical disease and motor performance. Importantly, electrophysiological measures revealed improved corpus callosal conduction and reduced axon refractoriness. This Ind-Cl treatment-induced functional remyelination was attributable to increased OL progenitor cell (OPC) and mature OL numbers. At the intracellular signaling level, transition of early to late OPCs requires ERK1/2 signaling, and transition of immature to mature OLs requires mTOR signaling; thus, the PI3K/Akt/mTOR pathway plays a major role in the late stages of OL differentiation and myelination. Indeed, therapeutic treatment of EAE mice with various ERβ agonists results in increased brain-derived neurotrophic factor (BDNF) and phosphorylated (p) Akt and p-mTOR levels. It is notable that while DPN's neuroprotective effects occur in the presence of peripheral and central inflammation, Ind-Cl is directly neuroprotective, as demonstrated by remyelination effects in the cuprizone-induced demyelination model, as well as immunomodulatory. Elucidating the mechanisms by which ER agonists and other directly remyelinating agents modulate endogenous OPC and OL regulatory signaling is critical to the development of effective remyelinating drugs. The discovery of signaling targets to induce functional remyelination will valuably contribute to the treatment of demyelinating neurological diseases, including MS, stroke, and traumatic brain and spinal cord injury.
authors.affiliation: Division of Biomedical Sciences, School of Medicine at the University of California, Riverside, United States.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Khalaj
authors.affiliation: Division of Biomedical Sciences, School of Medicine at the University of California, Riverside, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hasselmann
authors.affiliation: Division of Biomedical Sciences, School of Medicine at the University of California, Riverside, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Augello
authors.affiliation: Division of Biomedical Sciences, School of Medicine at the University of California, Riverside, United States.
authors.forename: Spencer
authors.initials: S
authors.lastname: Moore
authors.affiliation: Division of Biomedical Sciences, School of Medicine at the University of California, Riverside, United States; Neuroscience Graduate Program, University of California, Riverside, United States. Electronic address: seema.tiwari-woodruff@ucr.edu.
authors.forename: Seema K
authors.initials: SK
authors.lastname: Tiwari-Woodruff
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Axon degeneration; Demyelination; Estrogen receptor ligands; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Remyelination