UC Riverside

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease with no known etiology nor cure. Current immunomodulatory drugs reduce inflammation or prevent leukocyte egress from lymph nodes, but neither halt disease progression nor promote repair of damaged axons. Since oligodendrocyte (OL) death, neurodegeneration, and axonal pathology are prominent at all stages of MS, therapies that promote remyelination and repair are urgently needed. Estrogens have emerged as attractive candidates that meet those needs. Estrogens, synthetic or natural, exert their effects through two nuclear recpetors, estrogen receptor (ER)α and ERβ. However, while use of estrogens, acting primarily on ERα, produce significant deleterious side effects, including increasing risk of cancer and producing feminizing effects in males, selectively targeting ERβ using synthetic small molecules produces comparable therapeutic benefits. To investigate the mechanisms of ERβ-induced therapeutic benefits, a myelin oligodendrocyte glycoprotein- experimental autoimmune encephalomyelitis (MOG-EAE) animal model was utilized. First, two well studied and characterized ERβ ligands, diarylpropionitrile (DPN), and WAY 202041 (WAY) as well as recently established ERβ ligand, chloroindazole (IndCl) were assessed for their therapeutic efficacy in attenuating clinical EAE disease. All three ligands ameliorated clinical disease symptoms, increased oligodendrocyte (OL) numbers, and promoted functional remyelination of callosal axons in EAE. As IndCl proved to be the most efficacious and potent ERβ ligand, analogues of IndCl were developed and assayed for their role in immunomodulation and neuroprotection. Two analogues, IndCl-o-Cl and IndCl-o-Me attenuated clinical disease progression over time, increased mature OL numbers and enhanced myelination in the corpus callosum and white matter tracts of the spinal cord, similar to parent compound IndCl. These effects were partly mediated by reduced secretion of highly OL-toxic interferon (IFN)γ and IFNγ-inducible chemokine C-X-C motif 10 (CXCL10) by splenic mononuclear cell and increased chemokine CXCL1 production by both splenic leukocytes and thoracic spinal cord astrocytes. Aside from its role in neutrophil chemoattraction, astrocyte-derived CXCL1 acting through its cognate receptor, CXCR2, on OL lineage cells has been implicated in normal myelination by coordinating developmental OL progenitor cell (OPC) positioning, proliferation, and differentiation. The findings presented here provide novel insight in uncovering how ERβ ligands modulate CXCL1 production to initiate OPC proliferation, differentiation, and myelin repair; and will provide the foundation for future studies to develop novel therapies such as IndCl and analogues with similar immunomodulatory, remyelinating, and neuroprotective qualities that can offer targeted therapies to patients with MS and other demyelinating diseases.