Abstract
Pharmaceutical agents currently approved for the treatment of multiple sclerosis reduce relapse rates, but do not reverse or prevent neurodegeneration nor initiate myelin repair. The highly selective estrogen receptor (ER) β ligand chloroindazole (IndCl) shows particular promise promoting both remyelination while reducing inflammatory cytokines in the central nervous system of mice with experimental autoimmune encephalomyelitis. To optimize these benefits, we developed and screened seven novel IndCl analogues for their efficacy in promoting primary oligodendrocyte (OL) progenitor cell survival, proliferation, and differentiation in vitro by immunohistochemistry. Two analogues, IndCl-o-chloro and IndCl-o-methyl, induced proliferation and differentiation equivalent to IndCl and were selected for subsequent in vivo evaluation for their impact on clinical disease course, white matter pathology, and inflammation. Both compounds ameliorated disease severity, increased mature OLs, and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord. These effects were accompanied by reduced production of the OL toxic molecules interferon-γ and chemokine (C-X-C motif) ligand, CXCL10 by splenocytes with no discernable effect on central nervous system-infiltrating leukocyte numbers, while IndCl-o-methyl also reduced peripheral interleukin (IL)−17. In addition, expression of the chemokine CXCL1, which is associated with developmental oligodendrogenesis, was upregulated by IndCl and both analogues. Furthermore, callosal compound action potential recordings from analogue-treated mice demonstrated a larger N1 component amplitude compared to vehicle, suggesting more functionally myelinated fibers. Thus, the o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases.
Highlights
Multiple sclerosis (MS) is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with no known cause or cure
Primary OL progenitor cells (OPCs) prepared from mouse neonatal cortex were treated with one of seven IndCl analogues or control at a concentration of 10 nM24,25
In search of therapeutic agents capable of reversing the progression of MS, we discovered that IndCl, a novel highly selective ERβ ligand, reduces CNS inflammation, promotes remyelination, and ameliorates disease in the EAE and cuprizone models of MS10
Summary
Multiple sclerosis (MS) is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS) with no known cause or cure. The EAE model has been used to develop many of the currently approved MS treatments, including interferon (IFN)-β, glatiramer acetate, fingolimod, and the anti- cluster of differentiation (CD) 20 monoclonal antibody, ocrelizumab[1,2] These therapeutics attenuate inflammation, they neither prevent neurodegeneration nor initiate remyelination. These seven analogues, all of which exhibited ERβ-preferential binding affinities, were initially screened in primary OPC cultures for survival, proliferation and differentiation From this initial set, only two, IndCl-o-chloro (IndCl-o-Cl) and IndCl-o-methyl (IndCl-o-Me), showed activity comparable or superior to IndCl and were selected for in vivo testing in mice with EAE.
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