RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AßO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (90 µM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AßO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AßO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Lignanos , Fármacos Neuroprotectores , Ratones , Masculino , Animales , Péptidos beta-Amiloides/metabolismo , Memantina/farmacología , Antioxidantes/farmacología , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Lignanos/farmacología , Furanos/farmacología , Antiinflamatorios/farmacología , Fármacos Neuroprotectores/farmacología , Hipocampo/metabolismoRESUMEN
Studies have demonstrated that diet rich in cruciferous vegetables of the Brassicaceae family can reduce the risk of cardiovascular diseases and oxidative stress levels. Nasturtium officinale (Brassicaceae), commonly known as watercress is a perennial dicotyledonous plant usually found close to water. Although previous investigations have demonstrated the beneficial effects of watercress on hypercholesterolemia in animal studies, until now no such studies have been conducted with humans, up to this time. This study aimed to investigate whether overweight individuals were able to improve or maintain their serum lipid and oxidative stress markers when given standardized extract of Nasturtium officinale (SENO) as a supplement. This was a randomized, double-blind, and placebo-controlled trial conducted over 5 weeks. Thirty-four overweight people with physical disabilities were selected randomly to participate in this study and then they were assigned randomly to two groups, one treated with 750 mg//kg/d of SENO and the other treated with 750 mg/kg/d of placebo. The results indicated that SENO caused a significant improvement in the levels of low-density lipoprotein cholesterol, creatinine, and lipid peroxidation. However, SENO did not cause a significant statistical change in total serum cholesterol, triacylglycerol, and high-density lipoprotein levels; catalase, superoxide dismutase, creatinine, alanine aminotransferase, aspartate aminotransferase, and urea parameters. The present data might provide supportive evidence that SENO did not cause any harm and positively affected low-density lipoprotein cholesterol profile and creatinine as well as lipid peroxidation levels in the participants. Nevertheless, further studies are suggested to clarify the results presented in this clinical trial.
Asunto(s)
Suplementos Dietéticos/análisis , Metabolismo de los Lípidos/efectos de los fármacos , Nasturtium/química , Sobrepeso/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Adulto , Personas con Discapacidad , Método Doble Ciego , Femenino , Humanos , MasculinoRESUMEN
Although inflammation is a biological phenomenon that exists to protect the host against infections and/or related problems, its unceasing activation results in the aggravation of several medical conditions. Imidazoles, whether natural or synthetic, are molecules related to a broad spectrum of biological effects, including anti-inflammatory properties. In this study, we screened eight novel small molecules of the imidazole class synthesized by our research group for their in vitro anti-inflammatory activity. The effect of the selected molecules was confirmed in an in vivo inflammatory model. We also analyzed whether the effects were caused by inhibition of nuclear factor kappa B (NF-κB) transcription factor transmigration. Of the eight imidazoles tested, methyl 1-allyl-2-(4-fluorophenyl)-5-phenyl-1H-imidazole-4-acetate (8) inhibited nitric oxide metabolites and pro-inflammatory cytokine (TNF-α, IL-6, and IL-1ß) secretion in J774 macrophages stimulated with LPS. It also attenuated leukocyte migration and exudate formation in the pleural cavity of mice challenged with carrageenan. Furthermore, imidazole 8 reverted the oxidative stress pattern triggered by carrageenan in the pleural cavity by diminishing myeloperoxidase, superoxide dismutase, catalase, and glutathione S-transferase activities and reducing the production of nitric oxide metabolites and thiobarbituric acid-reactive substances. Finally, these effects can be attributed, at least in part, to the ability of this compound to prevent NF-κB transmigration. In this context, our results demonstrate that imidazole 8 has promising potential as a prototype for the development of a new anti-inflammatory drug to treat inflammatory conditions in which NF-κB and oxidative stress play a prominent role. Graphical Abstract á .
Asunto(s)
Antiinflamatorios/síntesis química , Diseño de Fármacos , Imidazoles/farmacología , Animales , Línea Celular , Imidazoles/síntesis química , Imidazoles/química , Ratones , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity.
Asunto(s)
Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Síndrome de Down/tratamiento farmacológico , Melatonina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Encéfalo/patología , Catalasa/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Cognición/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Modelos Animales de Enfermedad , Síndrome de Down/metabolismo , Síndrome de Down/patología , Miedo/efectos de los fármacos , Miedo/fisiología , Antígeno Ki-67/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Melatonina/sangre , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fármacos Neuroprotectores/sangre , Estrés Oxidativo/fisiología , Distribución Aleatoria , Superóxido Dismutasa/metabolismoRESUMEN
Previous studies have demonstrated that melatonin administration improves spatial learning and memory and hippocampal long-term potentiation in the adult Ts65Dn (TS) mouse, a model of Down syndrome (DS). This functional benefit of melatonin was accompanied by protection from cholinergic neurodegeneration and the attenuation of several hippocampal neuromorphological alterations in TS mice. Because oxidative stress contributes to the progression of cognitive deficits and neurodegeneration in DS, this study evaluates the antioxidant effects of melatonin in the brains of TS mice. Melatonin was administered to TS and control mice from 6 to 12 months of age and its effects on the oxidative state and levels of cellular senescence were evaluated. Melatonin treatment induced antioxidant and antiaging effects in the hippocampus of adult TS mice. Although melatonin administration did not regulate the activities of the main antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in the cortex or hippocampus, melatonin decreased protein and lipid oxidative damage by reducing the thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) levels in the TS hippocampus due to its ability to act as a free radical scavenger. Consistent with this reduction in oxidative stress, melatonin also decreased hippocampal senescence in TS animals by normalizing the density of senescence-associated ß-galactosidase positive cells in the hippocampus. These results showed that this treatment attenuated the oxidative damage and cellular senescence in the brain of TS mice and support the use of melatonin as a potential therapeutic agent for age-related cognitive deficits and neurodegeneration in adults with DS.
Asunto(s)
Antioxidantes/farmacología , Síndrome de Down/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Animales , Senescencia Celular , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Melatonina/administración & dosificación , Ratones , Oxidación-Reducción/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Alcohol abuse during pregnancy leads to intellectual disability and morphological defects in the offspring. The aim of this study was to determine the effect of chronic maternal ethanol (EtOH) consumption during pregnancy and lactation on glutamatergic transmission regulation, energy deficit, and oxidative stress in the hippocampus of the offspring. METHODS: EtOH was administered to dams in drinking water at increasing doses (2 to 20%) from the gestation day 5 to lactation day 21. EtOH and tap water intake by treated and control groups, respectively, were measured daily. RESULTS: Results showed that EtOH exposure does not affect fluid intake over the course of pregnancy and lactation. The toxicity of maternal exposure to EtOH was demonstrated by decreased offspring body weight at experimental age, on postnatal day 21. Moreover, maternal EtOH exposure decreased (45) Ca(2+) influx in the offspring's hippocampus. Corroborating this finding, EtOH increased both Na(+) -dependent and Na(+) -independent glial [(14) C]-glutamate uptake in hippocampus of immature rats. Also, maternal EtOH exposure decreased glutamine synthetase activity and induced aspartate aminotransferase enzymatic activity, suggesting that in EtOH-exposed offspring hippocampus, glutamate is preferentially used as a fuel in tricarboxylic acid cycle instead of being converted into glutamine. In addition, EtOH exposure decreased [U-14C]-2-deoxy-D-glucose uptake in offspring hippocampus. CONCLUSIONS: The decline in glucose transport coincided with increased lactate dehydrogenase activity, suggesting an adaptative response in EtOH-exposed offspring hippocampus, using lactate as an alternative fuel. These events were associated with oxidative damage, as demonstrated by changes in the enzymatic antioxidant defense system and lipid peroxidation. Taken together, the results demonstrate that maternal exposure to EtOH during pregnancy and lactation impairs glutamatergic transmission, as well as inducing oxidative stress and energy deficit in immature rat hippocampus.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Hipocampo/efectos de los fármacos , Exposición Materna , Neuroglía/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Calcio/metabolismo , Radioisótopos de Carbono , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Lactancia , Neuroglía/metabolismo , Embarazo , Cintigrafía , Ratas , Ratas Wistar , Sodio/metabolismoRESUMEN
Resumen La generación excesiva de especies reactivas de oxígeno está implicada en la patogénesis de la hepatitis C. El objetivo de este estudio fue evaluar el estado antioxidante de la sangre en pacientes infectados por VHC tratados o sin tratamiento con la terapia estándar, antes y después de la complementación con vitaminas E, C y Zinc. Se evaluaron los biomarcadores de estrés oxidativo en sangre de tres grupos de pacientes: grupo 1 - controles, grupo 2 - pacientes con VHC sin tratamiento examinados antes y después de una complementación diaria de antioxidantes (800mg de vitamina E, 500mg de vit. C, y 40mg de zinc) durante 6 meses y grupo 3 - pacientes con VHC tratados con interferón pegilado combinado con ribavirina, también examinados antes y después de la misma complementación diaria con antioxidantes. Antes del tratamiento antiviral los pacientes con VHC mostraban una mayor actividad del superóxido dismutasa, la catalasa y el glutatión peroxidasa y una actividad reducida de la glutatión reductasa, (..) (AU)
Abstract Reactive oxygen species (ROS) overgeneration is involved in the pathogenesis of hepatitis C. The aim of this study was to evaluate the antioxidant status in the blood of HCV infected patients treated or not with standard therapy before and after supplementation of vitamins E, C and zinc. Biomarkers of oxidative stress were evaluated in the blood of three groups of patients: group 1 - controls; group 2 - HCV patients without treatment examined before and after a daily antioxidant supplementation (vitamin E 800mg, C 500mg and zinc 40mg) for 6 months; and group 3 - HCV patients treated with pegylated interferon combined with ribavirin, also examined before and after the same antioxidant supplementation. Before antiviral treatment HCV patients showed enhanced superoxide dismutase, catalase and glutathione peroxidase activities and decreased glutathione reductase activity, while lipoperoxidation was increased and reduced glutathione showed decreased levels compared to controls. Treatment with standard therapy enhanced the activities of catalase and glutathione S-transferase, increased contents of protein carbonyl and promoted further reduced glutathione depletion. After antioxidant supplementation, decreased catalase and glutathione S-transferase activities, decreased lipoperoxidation in group 2, and increased reduced glutathione contents in both supplemented groups were detected. Before antioxidant supplementation, alanine aminotransferase and gamma glutamyl transferase contents showed significant increases in group 2. Conclusion: Untreated HCV patients and also those treated with the standard therapy are coping with a systemic oxidative stress. The antioxidant supplementation conferred an antioxidant protection to both supplemented groups attenuating oxidation processes related to the disease (AU)
Asunto(s)
Humanos , Antioxidantes/uso terapéutico , Estrés Oxidativo , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Ácido Ascórbico/uso terapéutico , ZincRESUMEN
UNLABELLED: Reactive oxygen species (ROS) overgeneration is involved in the pathogenesis of hepatitis C. The aim of this study was to evaluate the antioxidant status in the blood of HCV infected patients treated or not with standard therapy before and after supplementation of vitamins E, C and zinc. Biomarkers of oxidative stress were evaluated in the blood of three groups of patients: group 1 - controls; group 2 - HCV patients without treatment examined before and after a daily antioxidant supplementation (vitamin E 800 mg, C 500 mg and zinc 40 mg) for 6 months; and group 3 - HCV patients treated with pegylated interferon combined with ribavirin, also examined before and after the same antioxidant supplementation. Before antiviral treatment HCV patients showed enhanced superoxide dismutase, catalase and glutathione peroxidase activities and decreased glutathione reductase activity, while lipoperoxidation was increased and reduced glutathione showed decreased levels compared to controls. Treatment with standard therapy enhanced the activities of catalase and glutathione S-transferase, increased contents of protein carbonyl and promoted further reduced glutathione depletion. After antioxidant supplementation, decreased catalase and glutathione S-transferase activities, decreased lipoperoxidation in group 2, and increased reduced glutathione contents in both supplemented groups were detected. Before antioxidant supplementation, alanine aminotransferase and gamma glutamyl transferase contents showed significant increases in group 2. CONCLUSION: Untreated HCV patients and also those treated with the standard therapy are coping with a systemic oxidative stress. The antioxidant supplementation conferred an antioxidant protection to both supplemented groups attenuating oxidation processes related to the disease.