Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects

• Published in: The Journal of steroid biochemistry and molecular biology 2016-06, Vol.160, p.43-52
• Main Authors: Khalaj, Anna J., Hasselmann, Jonathan, Augello, Catherine, Moore, Spencer, Tiwari-Woodruff, Seema K.
• Format: Article
• Language: English
• Subjects: Animals; Axon degeneration; Demyelination; Drug Discovery - methods; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Estrogen Receptor beta - agonists; Estrogen Receptor beta - metabolism; Estrogen receptor ligands; Estrogens - metabolism; Experimental autoimmune encephalomyelitis; Humans; Ligands; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Myelin Sheath - drug effects; Myelin Sheath - metabolism; Myelin Sheath - pathology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oligodendroglia - pathology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Remyelination; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2016.01.006

•Pregnancy is associated with remission in patients with multiple sclerosis (MS).•Estrogen receptor β agonists stimulate functional remyelination in MS mouse models.•Some ERβ agonists activate PI3K/Akt/mTOR signaling pathways in oligodendrocytes to stimulate remyelination.•ERβ agonists induce multiple therapeutic effects on the CNS and are devoid of negative side effects associated with ERα agonists.•ERβ agonists represent promising potential novel therapeutics for MS. 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 de