RESUMEN
The brain could be exposed to irradiation as part of a nuclear accident, radiological terrorism (dirty bomb scenario) or a medical radiological procedure. In the context of accidents or terrorism, there is considerable interest in compounds that can mitigate radiation-induced injury when treatment is initiated a day or more after the radiation exposure. As it will be challenging to determine the radiation exposure an individual has received within a relatively short time frame, it is also critical that the mitigating agent does not negatively affect individuals, including emergency workers, who might be treated, but who were not exposed. Alterations in hippocampus-dependent cognition often characterize radiation-induced cognitive injury. The catalytic ROS scavenger EUK-207 is a member of the class of metal-containing salen manganese (Mn) complexes that suppress oxidative stress, including in the mitochondria, and have been shown to mitigate radiation dermatitis, promote wound healing in irradiated skin, and mitigate vascular injuries in irradiated lungs. As the effects of EUK-207 against radiation injury in the brain are not known, we assessed the effects of EUK-207 on sham-irradiated animals and the ability of EUK-207 to mitigate radiation-induced cognitive injury. The day following irradiation or sham-irradiation, the mice started to receive EUK-207 and were cognitively tested 3 months following exposure. Mice irradiated at a dose of 15Gy showed cognitive impairments in the water maze probe trial. EUK-207 mitigated these impairments while not affecting cognitive performance of sham-irradiated mice in the water maze probe trial. Thus, EUK-207 has attractive properties and should be considered an ideal candidate to mitigate radiation-induced cognitive injury.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Compuestos Organometálicos/uso terapéutico , Traumatismos Experimentales por Radiación/complicaciones , Análisis de Varianza , Animales , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta en la Radiación , Miedo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Superóxido Dismutasa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Potential mechanisms of Passiflora incarnata extracts and the effect of extraction methods on ingredients and biological effects were explored. Using the same batch of plant material, total flavonoid yields as measured by high-performance liquid chromatography coupled to diode array detection (HPLC-DAD) increased substantially with hot versus cold extraction methods. Whole Passiflora extract induced prominent, dose-dependent direct GABA(A) currents in hippocampal slices, but the expected modulation of synaptic GABA(A) currents was not seen. GABA was found to be a prominent ingredient of Passiflora extract, and GABA currents were absent when amino acids were removed from the extract. Five different extracts, prepared from a single batch of Passiflora incarnata, were administered to CF-1 mice for 1 week in their drinking water prior to evaluation of their behavioral effects. Anticonvulsant effects against PTZ-induced seizures were seen in mice that received 2 of the 5 Passiflora extracts. Instead of the anxiolytic effects described by others, anxiogenic effects in the elevated plus maze were seen in mice receiving any of the 5 Passiflora extracts.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Ansiedad/tratamiento farmacológico , Agonistas del GABA/uso terapéutico , Hipocampo/efectos de los fármacos , Passiflora/química , Extractos Vegetales/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/farmacología , Ansiedad/inducido químicamente , Relación Dosis-Respuesta a Droga , Flavonoides/efectos adversos , Flavonoides/farmacología , Flavonoides/uso terapéutico , Agonistas del GABA/farmacología , Hipocampo/fisiología , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos , Pentilenotetrazol , Fitoterapia , Extractos Vegetales/efectos adversos , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Temperatura , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Understanding cognitive aging is becoming more important as the elderly population grows. Here, the effects of age and sex on learning and memory performance were compared in female and male young (3-4 months old) middle-aged (10-12 months old) and old (18-20 months old) wild-type C57BL/6J mice. Old males and females performed worse than young or middle-aged mice in novel location, but not novel object recognition tasks. Old mice, of both sexes, also showed impaired spatial water maze performance during training compared with young or middle-aged mice, however only old females failed to show robust spatial bias during probe trials. While there was no age-difference in passive avoidance performance for males, females showed an age-related decline. There was no difference in cognitive performance between young and middle-age mice of either sex on any task. Cognitive performance was associated with alterations in immunoreactivity of microtubule-associated protein 2-positive dendrites and synaptophysin-positive pre-synaptic terminals in hippocampal CA1, CA3, and dentate, entorhinal cortex, and central nucleus of amygdala. Overall, microtubule-associated protein 2 immunoreactivity was increased in old females compared with both young and middle-age females with no significant difference in males. In contrast, synaptophysin immunoreactivity increased from young to middle-age in females, and from middle-age to old in males; females had higher levels of synaptophysin immunoreactivity than males in middle-age only. Elevated levels of microtubule-associated protein 2 and synaptophysin may constitute a compensatory response to age-related functional decline in mice.