ABSTRACT
Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.
Subject(s)
Benztropine/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Models, Biological , Multiple Sclerosis/drug therapy , Myelin Sheath/drug effects , Oligodendroglia/drug effects , Regeneration/drug effects , Animals , Antiparkinson Agents/pharmacology , Antiparkinson Agents/therapeutic use , Benztropine/pharmacology , Cell Differentiation/drug effects , Coculture Techniques , Cuprizone/pharmacology , Cuprizone/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Fingolimod Hydrochloride , Immune System/drug effects , Immune System/immunology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Myelin Proteolipid Protein/pharmacology , Myelin Sheath/metabolism , Myelin Sheath/pathology , Oligodendroglia/cytology , Oligodendroglia/metabolism , Oligodendroglia/pathology , Optic Nerve/cytology , Propylene Glycols/pharmacology , Propylene Glycols/therapeutic use , Rats , Receptor, Muscarinic M1/antagonists & inhibitors , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M3/antagonists & inhibitors , Receptor, Muscarinic M3/metabolism , Recurrence , Sphingosine/analogs & derivatives , Sphingosine/pharmacology , Sphingosine/therapeutic use , Stem Cells/cytology , Stem Cells/drug effectsABSTRACT
The identification of factors that promote ß cell proliferation could ultimately move type 1 diabetes treatment away from insulin injection therapy and toward a cure. We have performed high-throughput, cell-based screens using rodent ß cell lines to identify molecules that induce proliferation of ß cells. Herein we report the discovery and characterization of WS6, a novel small molecule that promotes ß cell proliferation in rodent and human primary islets. In the RIP-DTA mouse model of ß cell ablation, WS6 normalized blood glucose and induced concomitant increases in ß cell proliferation and ß cell number. Affinity pulldown and kinase profiling studies implicate Erb3 binding protein-1 and the IκB kinase pathway in the mechanism of action of WS6.
