RESUMEN
Calcineurin inhibitors such as cyclosporine A and FK506 have been used for transplant therapy and treatment of autoimmune diseases. However, the inhibition of calcineurin outside the immune system has a number of side effects, including hyperglycemia. In the search for safer drugs, we developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide provided immunosuppression for fully mismatched islet allografts in mice. In addition, it did not affect insulin secretion, whereas FK506 caused a dose-dependent decrease in insulin secretion. Cell-permeable peptides can thus provide a new strategy for drug development and may eventually be useful clinically.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Inmunosupresores/farmacología , Trasplante de Islotes Pancreáticos , Proteínas Nucleares , Proteínas Recombinantes de Fusión/farmacología , Factores de Transcripción/antagonistas & inhibidores , Animales , Proteínas de Unión al ADN/metabolismo , Supervivencia de Injerto , Humanos , Inmunosupresores/metabolismo , Insulina/metabolismo , Secreción de Insulina , Interleucina-2/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Células Jurkat , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Factores de Transcripción NFATC , Oligopéptidos/química , Oligopéptidos/genética , Oligopéptidos/metabolismo , Péptidos , Permeabilidad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tacrolimus/metabolismo , Tacrolimus/farmacología , Factores de Transcripción/metabolismo , Trasplante HomólogoRESUMEN
In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-beta (Abeta) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Abeta40 and Abeta42 were used for immunocytochemical analyses, Abeta42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Abeta-oligomer. In comparison to the Abeta42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Abeta42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=- 0.61, p<0.02). Together with recent evidence that the Abeta peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Abeta may be a compensatory response in neurons to oxidative stress in Alzheimer disease.