RESUMO
Two types of interventions to remyelinate the adult demyelinated central nervous system were investigated in heterozygous transgenic mice overexpressing the proteolipid protein gene. 1) A cocktail of trophic factors, "TS1," was directed toward the activation of the endogenous pool of neural progenitors to increase the number of myelinating oligodendrocytes (OL) in the brain. 2) A combinatorial approach in which OL progenitors were coinjected with TS1 into the corpus callosum of wild-type and He4e transgenic mice that displayed hindlimb paralysis. The levels of locomotor ability in these mice were evaluated after a single treatment. The data showed that a single administration of either one of the interventions had similar therapeutic effects, alleviating the symptoms of demyelination and leading to the recovery of hindlimb function. Histological and immunofluorescent examination of brain sections showed extensive remyelination that was sufficient to reverse hindlimb paralysis in transgenic mice. When the interventions were administered prior to hindlimb paralysis, He4e mice were able to walk up to 1 year of age without paralysis.
Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Proteína Proteolipídica de Mielina/metabolismo , Recuperação de Função Fisiológica/fisiologia , Amidinas/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Corpo Caloso/metabolismo , Corpo Caloso/transplante , Meios de Cultivo Condicionados/farmacologia , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/cirurgia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/fisiologia , Gangliosídeos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteínas de Filamentos Intermediários/genética , Camundongos , Camundongos Transgênicos , Microscopia Confocal/métodos , Proteína Básica da Mielina/metabolismo , Proteína Proteolipídica de Mielina/genética , Proteínas do Tecido Nervoso/genética , Nestina , Proteínas de Neurofilamentos/metabolismo , Neuroglia/química , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/genética , Fatores de TempoRESUMO
Myelin-deficient (md) rats and their unaffected littermates were injected at postnatal day 4 either with a single dose of transferrin (Tf) or insulin-like growth factor one (IGF-1) singly or combined. Two weeks later, their brains were perfused and coronal sections were analyzed for MBP by in situ hybridization and for transferrin and myelin basic protein (Tf and MBP) by double immunofluorescence. Each of the factors separately had an effect on mutant animals as seen by both increased OL maturation, and MBP mRNA and protein synthesis. The combination of factors resulted in a profound enhancement of the myelinogenic properties of oligodendrocytes (OL) with a consequent increase in the number of MBP-labeled fibers. The brains of unaffected littermates also responded to growth factor(s) injection either by increasing myelination in some brain areas or by regulating the synthesis of MBP in OL. Using rat OL cultures we studied the site of transferrin action for the expression of MBP gene. We found by run off transcription that the MBP mRNA was significantly increased at the nuclear level but the PLP message was unaffected. Thus, transferrin selectively regulates MBP at the transcriptional level and together with IGF-1 synergizes to increase both the maturation and myelinogenic properties of md and normal OL.