RESUMO
Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Óxidos N-Cíclicos/uso terapêutico , Indóis/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Antioxidantes/administração & dosagem , Antioxidantes/química , Aspirina/farmacologia , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/síntese química , Citocromos c/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/administração & dosagem , Indóis/síntese química , Indóis/farmacologia , Intestino Delgado/irrigação sanguínea , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Simulação de Dinâmica Molecular , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We describe several novel curcumin analogues that possess both anti-inflammatory antioxidant properties and thrombolytic activities. The therapeutic efficacy of these curcumin analogues was verified in a mouse ear edema model, a rat arterial thrombosis assay, a free radical scavenging assay performed in PC12 cells, and in both in vitro and in vivo ischemia/reperfusion models. Our findings suggest that their protective effects partially reside in maintenance of optimal mitochondrial function.