RESUMO
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.
Assuntos
Benzotropina/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Modelos Biológicos , Esclerose Múltipla/tratamento farmacológico , Bainha de Mielina/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Benzotropina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cocultura , Cuprizona/farmacologia , Cuprizona/uso terapêutico , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Feminino , Cloridrato de Fingolimode , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Proteína Proteolipídica de Mielina/farmacologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Nervo Óptico/citologia , Propilenoglicóis/farmacologia , Propilenoglicóis/uso terapêutico , Ratos , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Recidiva , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacosRESUMO
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.