RESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Indoles/uso terapéutico , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Antioxidantes/administración & dosificación , Antioxidantes/química , Aspirina/farmacología , Óxidos N-Cíclicos/administración & dosificación , Óxidos N-Cíclicos/síntesis química , Citocromos c/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Indoles/administración & dosificación , Indoles/síntesis química , Indoles/farmacología , Intestino Delgado/irrigación sanguínea , Intestino Delgado/metabolismo , Intestino Delgado/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Endogámicos ICR , Mitocondrias/metabolismo , Simulación de Dinámica Molecular , Infiltración Neutrófila/efectos de los fármacos , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Antiinflamatorios/farmacología , Curcumina/análogos & derivados , Depuradores de Radicales Libres/farmacología , Mitocondrias/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Curcumina/farmacología , Curcumina/uso terapéutico , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Edema/prevención & control , Ensayo de Inmunoadsorción Enzimática , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/uso terapéutico , Células Endoteliales de la Vena Umbilical Humana , Interleucina-6/sangre , Ratones , Microscopía Fluorescente , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Teoría Cuántica , Ratas , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/reperfusion (I/R) injury, cardiovascular disorders and neurodegenerative diseases. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel kyotorphin-nitroxide hybrid molecules, and examined their free radical scavenging activities, in addition to their anti-inflammatory and analgesic activities. We have further characterized these compounds in a simulated I/R cellular model. Our findings suggest that the protective effects of kyotorphin-nitroxides partially reside in maintaining optimal mitochondrial function.
