RESUMEN
Superoxide dismutase/catalase mimetics, such as salen Mn complexes and certain metalloporphyrins, catalytically neutralize reactive oxygen and nitrogen species, which have been implicated in the pathogenesis of many serious diseases. Both classes of mimetic are protective in animal models of oxidative stress. However, only AEOL11207 and EUK-418, two uncharged Mn porphyrins, have been shown to be orally bioavailable. In this study, EUK-418 and several new analogs (the EUK-400 series) were synthesized and shown to exhibit superoxide dismutase, catalase, and peroxidase activities in vitro. Some also protected PC12 cells against staurosporine-induced cell death. All EUK-400 compounds were stable in simulated gastric fluid, and most were substantially more lipophilic than the salen Mn complexes EUK-189 and EUK-207, which lack oral activity. Pharmacokinetics studies demonstrate the presence of all EUK-400 series compounds in the plasma of rats after oral administration. These EUK-400 series compounds are potential oral therapeutic agents for cellular damage caused by oxidative stress.
Asunto(s)
Catalasa/metabolismo , Manganeso/metabolismo , Metaloporfirinas/administración & dosificación , Metaloporfirinas/metabolismo , Superóxido Dismutasa/metabolismo , Administración Oral , Animales , Biocatálisis , Disponibilidad Biológica , Materiales Biomiméticos/administración & dosificación , Materiales Biomiméticos/metabolismo , Materiales Biomiméticos/farmacocinética , Materiales Biomiméticos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Metaloporfirinas/farmacocinética , Metaloporfirinas/farmacología , Células PC12 , Ratas , Estaurosporina/farmacologíaRESUMEN
We tested the effects of salen manganese (Salen-Mn) complexes, which are scavengers of reactive oxygen species exhibiting superoxide dismutase and catalase activities on the rejection of and alloresponse to fully allogeneic skin grafts in mice. We showed that pre-transplant treatment of C57Bl/6 donor skin or of BALB/c recipients with Salen-Mn complexes significantly delayed allograft rejection. ELISPOT analysis of alloimmune response of treated mice revealed a significant reduction of the frequency of type 1 cytokine (pro-inflammatory) producing T-cells, while the number of activated T-cells producing type 2 cytokines was elevated. In addition, anti-oxidative treatment of graft recipients resulted in a profound inhibition of their donor-specific cytotoxic T-cell response. Our results indicate that salen manganese complexes mediate their effect on graft rejection both by reducing the susceptibility of graft tissue to ROS-mediated injury and by exerting an anti-inflammatory effect in recipients.
Asunto(s)
Depuradores de Radicales Libres/farmacología , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Manganeso/farmacología , Especies Reactivas de Oxígeno/metabolismo , Trasplante de Piel/inmunología , Animales , Catalasa/metabolismo , Catálisis/efectos de los fármacos , Citocinas/biosíntesis , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Rechazo de Injerto/inmunología , Técnicas In Vitro , Mediadores de Inflamación/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Inmunológicos , Superóxido Dismutasa/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Trasplante HomólogoRESUMEN
Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by approximately 50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species.
Asunto(s)
Envejecimiento/psicología , Antioxidantes/uso terapéutico , Encéfalo/metabolismo , Discapacidades para el Aprendizaje/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Compuestos Organometálicos/uso terapéutico , Salicilatos/uso terapéutico , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Animales , Antioxidantes/farmacología , Reacción de Prevención/efectos de los fármacos , Biomarcadores , Encéfalo/efectos de los fármacos , Encéfalo/patología , Catalasa , Electrochoque , Miedo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/patología , Peroxidación de Lípido/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Proteínas del Tejido Nervioso/metabolismo , Compuestos Organometálicos/farmacología , Oxidación-Reducción , Estrés Oxidativo , Dimensión del Dolor , Especies Reactivas de Oxígeno/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Salicilatos/farmacología , Superóxido Dismutasa , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisRESUMEN
Synthetic catalytic scavengers of reactive oxygen species (ROS) may have broad clinical applicability. In previous papers, two salen-manganese complexes, EUK-8 and EUK-134, had superoxide dismutase (SOD) and catalase activities and prevented ROS-associated tissue injury. This study describes two series of salen-manganese complexes, comparing catalytic ROS scavenging properties and cytoprotective activities. The compounds vary widely in ability to scavenge hydrogen peroxide, with this activity most influenced by salen ring alkoxy substitution and aromatic bridge modifications. In contrast, all compounds show comparable SOD activities. The most active alkoxy-substituted catalase mimetics protected cultured cells from hydrogen peroxide, and a subset of these were also neuroprotective in a rodent stroke model. Thus, structural modification of the prototype EUK-8 yields compounds with enhanced catalase activity and, in turn, biological effectiveness. This supports the concept that salen-manganese complexes represent a class of SOD and, in particular, catalase mimetics potentially useful against ROS-associated diseases.