RESUMO
Multiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In the present work, we used microglial modulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin-rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS.
Assuntos
Doenças Desmielinizantes/metabolismo , Microglia/metabolismo , Receptores de Fator Estimulador de Colônias/antagonistas & inibidores , Receptores de Fator Estimulador de Colônias/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Benzotiazóis/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/ultraestrutura , Bromodesoxiuridina/metabolismo , Cuprizona/toxicidade , Citocinas/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Microglia/ultraestrutura , Microscopia Eletrônica de Transmissão , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ácidos Picolínicos/uso terapêutico , Receptores de Fator Estimulador de Colônias/genética , Fatores de TempoRESUMO
The clinical course and intestinal absorption studies of a female infant who developed diarrhea after cessation of breast feeding, mood changes, and intermittently had mild perioral and perianal rashes are described. She showed a partial response to a pancreatic enzyme preparation which was attributed to its content of a zinc-binding ligand, picolinic acid. Complete recovery occurred on pharmacologic doses of zinc. Exacerbation occurred twice upon withdrawal of the oral zinc medication. The zinc concentrations of plasma and intestinal mucosa were normal.