Significance: In the search for effective multiple sclerosis treatment, much effort has been invested in estrogens and estrogen receptor (ER) agonists because of their neuroprotective benefits. However, because estrogens can produce ERα-based feminizing effects and cancer, ERβ agonists represent more desirable therapeutic candidates. The structurally unique ERβ ligand indazole chloride (Ind-Cl), a halogen-substituted phenyl-2H-indazole core, is a preclinical development candidate with a strong dossier. Our results indicate that Ind-Cl is effective in functionally ameliorating disease even when treatment is initiated at peak experimental autoimmune encephalomyelitis clinical disease. Ind-Cl’s immunomodulatory and direct remyelinating effects result in motor dysfunction amelioration. These findings support Ind-Cl's potential to provide unique therapeutic benefits to patients with multiple sclerosis, as well as patients affected by other demyelinating disorders.

Significance: Multiple sclerosis (MS) is a debilitating neurodegenerative disease characterized by inflammation and demyelination. Immunomodulatory agents slow, but do not prevent, disease progression and offer only indirect neuroprotection. The estrogen receptor β (ERβ) ligand diarylpropionitrile (DPN) has direct neuroprotective effects in a mouse model of MS by stimulating endogenous myelination. Here we elucidate the cell type(s) mediating DPN’s effects. Conditional knockout of ERβ in oligodendrocyte (OL) lineage cells prevented DPN-induced improvement in clinical disease and myelination, partially prevented callosal conduction improvement, and prevented activation of a pathway implicated in OL survival/axon myelination. Our results indicate that DPN-conferred neuroprotection in a mouse model of MS is mediated by ERβ in OLs and inform highly targeted pharmacotherapeutic approaches to MS treatment.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV bothin vitroandin vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs.In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell deathin vitroand reduced viral burdenin vivoin animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity.