RESUMO
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Imunossupressores/farmacologia , Transplante de Rim , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Imunossupressores/toxicidade , Interleucina-2/imunologia , Janus Quinase 3 , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Teste de Cultura Mista de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Miocárdio/metabolismo , Piperidinas , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Pirróis/toxicidade , Transplante Heterotópico , Transplante Homólogo , Células Tumorais CultivadasRESUMO
Neurons in the medial superior olive encode interaural temporal disparity, and their receptive fields indicate the location of a sound source in the azimuthal plane. It is often assumed that the projections of these neurons transmit the receptive field information about azimuth from point to point, much like the projections of the retina to the brain transmit the position of a visual stimulus. Yet this assumption has never been verified. Here, we use physiological and anatomical methods to examine the projections of the medial superior olive to the inferior colliculus for evidence of a spatial topography that would support transmission of azimuthal receptive fields. The results show that this projection does not follow a simple point-to-point topographical map of receptive field location. Thus, the representation of sound location along the azimuth in the inferior colliculus most likely relies on a complex, nonlinear map.
Assuntos
Percepção Auditiva , Colículos Inferiores/citologia , Núcleo Olivar/citologia , Estimulação Acústica , Animais , Vias Auditivas , Transporte Axonal , Axônios/ultraestrutura , Mapeamento Encefálico , Gatos , Dextranos/administração & dosagem , Colículos Inferiores/fisiologia , Cinética , Neurônios/metabolismo , Núcleo Olivar/fisiologia , Terminações Pré-Sinápticas/ultraestruturaRESUMO
The efficacy of a novel, nonpeptidic, caspase 3/7-selective inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (MMPSI) for reducing ischemic injury in isolated rabbit hearts or cardiomyocytes was evaluated. MMPSI (0.1-10 microM) evoked a concentration-dependent reduction in infarct size (up to 56% vs. control; IC(50)=0.2 microM). Furthermore, apoptosis (DNA laddering, soluble nucleosomes) was reduced in the ischemic area-at-risk. MMPSI inhibited recombinant human caspase-3 with an IC(50)=1.7 microM. Apoptosis in H9c2 cells after 16-h simulated ischemia and 2-h simulated reperfusion was significantly reduced by MMPSI in a concentration-dependent manner (IC(50)=0.5 microM); similar effects were observed in isolated adult rabbit cardiomyocytes (IC(50)=1.5 microM). These data support an important role for caspase-3/7 in mediating myocardial ischemic injury. Furthermore, these data indicate that cardioprotection via caspase-3/7 inhibition is attainable via a small molecule (nonpeptidic) inhibitor, a necessary step in making this approach therapeutically viable.