RESUMO
Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process.
Assuntos
Creatina/uso terapêutico , Doença de Huntington/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Nucleares/genética , Animais , Animais Geneticamente Modificados , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Atrofia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Creatina/administração & dosagem , Creatina/metabolismo , Cruzamentos Genéticos , Suplementos Nutricionais , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagemRESUMO
The cornified envelope of keratinocytes is an insoluble structure formed beneath the plasma membrane at the base of the stratum corneum. It is made by cross-linking precursor proteins by a membrane-associated transglutaminase. We have prepared monoclonal antibodies to the cornified envelope of cultured human keratinocytes and used these to identify precursor proteins using Western blotting. We have uncovered a number of precursors including involucrin and a 195 kD membrane-associated protein, which had previously been reported. Antibodies to these precursors, with the exception of the one to involucrin, reacted with the epidermis of other mammalian species, suggesting structural conservation in at least some envelope components.
