Acute Administration of Diazepam Provokes Redox Homeostasis Imbalance in the Rat Brain: Prevention by Simvastatin.

We investigated the effects of acute diazepam (DZP) administration on thiobarbituric acid-reactive substance (TBARS) levels, protein carbonyl content, and on the activities of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase in the brain of rats. Additionally, we investigated the antioxidant role of chronic pretreatment with simvastatin on the effects provoked by DZP. Simvastatin was administered (1 or 10 mg/kg by oral gavage) for 30 days. On the 30th day of treatment, groups were randomized and DZP was administered (0.5 or 1.0 mg/kg by intraperitoneal injection). Control groups received saline. Results showed that DZP enhanced TBARS levels and protein carbonyl content and altered enzymatic activity in the brain of rats. Simvastatin prevented most of the alterations caused by DZP on the oxidative stress parameters. Data indicate that DZP administration causes an oxidative imbalance in the brain areas studied; however, in the presence of simvastatin, some of these alterations in oxidative stress were prevented.

Differential in vitro effects of homoarginine on oxidative stress in plasma, erythrocytes, kidney and liver of rats in the absence and in the presence α-tocopherol, ascorbic acid or L-NAME.

In the present study, we evaluated the in vitro effects of homoarginine (hArg) at 1, 10 and 20 µM on thiobarbituric acid-reactive substances (TBA-RS), total sulfhydryl content and on the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in plasma, erythrocytes, kidney and liver of rats (60 days old). We also investigated the influence of the antioxidants (each at 1 mM) α-tocopherol and ascorbic acid, as well as of the nitric oxide synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) at 1 mM, on the effects elicited by hArg on the parameters tested. In plasma, hArg at concentrations of 10 and 20 µM decreased moderately the total sulfhydryl content. At 20 µM, hArg enhanced moderately TBA-RS in the plasma. In plasma, the effects of hArg (20 µM) on TBA-RS and total thiol content were abolished by α-tocopherol, ascorbic acid and L-NAME. At all concentrations tested, hArg did not exert any effect on CAT, SOD or GSH-Px activity in the erythrocytes. In the kidney, hArg exerted effects only at 20 µM and in a different manner: TBA-RS levels increased and total thiol content and CAT activity decreased, while SOD and GSH-Px activity increased. In the renal medulla, α-tocopherol and ascorbic acid but not L-NAME abolished the effects of hArg (20 µM) on TBA-RS, while all agents inhibited the hArg-induced increase in SOD activity. In the renal cortex, α-tocopherol, ascorbic acid and L-NAME abolished the effects of hArg (20 µM) on the total sulfhydryl content and GSH-Px activity, but L-NAME did not reverse the inhibitory effects of hArg on CAT activity. In the liver, no effects of hArg were observed of all biomarkers measured. At the pathologically high concentration of 20 µM, as it may occur in plasma in hyperargininemia, hArg may enhance lipid peroxidation and thiol oxidation and inhibit CAT activity, but may increase SOD and GSH-Px activity predominantly in the kidney.

Ferulic acid chronic treatment exerts antidepressant-like effect: role of antioxidant defense system.

Oxidative stress has been claimed a place in pathophysiology of depression; however, the details of the neurobiology of this condition remains incompletely understood. Recently, treatments employing antioxidants have been thoroughly researched. Ferulic acid (FA) is a phenolic compound with antioxidant and antidepressant-like effects. Herein, we investigated the involvement of the antioxidant activity of chronic oral FA treatment in its antidepressant-like effect using the tail suspension test (TST) and the forced swimming test (FST) in mice. The modulation of antioxidant system in blood, hippocampus and cerebral cortex was assessed after stress induction through TST and FST. Our results show that FA at the dose of 1 mg/kg has antidepressant-like effect without affecting locomotor activity. The stress induced by despair tests was able to decrease significantly the activities of superoxide dismutase (SOD) in the blood, catalase (CAT) in the blood and cerebral cortex and glutathione peroxidase (GSH-Px) in the cerebral cortex. Thiobarbituric acid-reactive substances (TBA-RS) levels were increased significantly in the cerebral cortex. Furthermore, the results show that FA was capable to increase SOD, CAT and GSH-Px activities and decrease TBA-RS levels in the blood, hippocampus and cerebral cortex. These findings demonstrated that FA treatment in low doses is capable to exert antidepressant-like effect with the involvement of the antioxidant defense system modulation.

Protective effect of Myrcia pubipetala Miq. against the alterations in oxidative stress parameters in an animal model of depression induced by corticosterone.

Depression is a debilitating disorder in humans that significantly affects quality of life. As such, alternative therapies are highly sought after by patients seeking treatment for depression. Experimentally, the chronic administration of corticosterone (CORT) in rodents has been reported to promote depressive-like behaviors. Herein, animals received saline or CORT for 21 days and, during the last 7 days, they were treated with the crude hydroalcoholic extract (CHE) of Myrcia pubipetala Miq (50, 100 or 150 mg/Kg), or vehicle (distilled water), by oral route. After 24 h, animals were subjected to the open field (OFT) and forced swimming tests (FST), and then sacrificed for the removal of the hippocampus and cerebral cortex for biochemical analysis. Results showed enhanced catalase (CAT) and superoxide dismutase (SOD) activities, as well as an elevated formation of thiobarbituric acid reactive substances (TBARS), in the cerebral cortex of CORT-treated mice. The chronic administration of the CHE (100 and 150 mg/Kg) reduced TBARS and the increased total sulfhydryl content, and also reversed the increase in TBARS induced by CORT. In the hippocampus, CORT increased CAT and SOD activities and reduced glutathione peroxidase (GSH-Px) (C) activity, while Myrcia pubipetala Miq. CHE (100 and 150 mg/Kg) increased GSH-Px activity when administered alone and reversed decreased GSH-Px (100 and 150 mg/Kg) activity when given during CORT administration. Neither CORT administration nor CHE treatment significantly altered the immobility time of the animals in FST and no changes were observed in the locomotor activity of the animals in the OFT. Findings indicate that the CHE of Myrcia pubipetala Miq. exerts antioxidant effects in the cerebral cortex and hippocampus of mice induced to depression by CORT. Since phenolic compounds are reported to have antioxidant effects in this species, the effects of the CHE may be, at least in part, mediated by the presence of these compounds in Myrcia extract.

Neuroinflammation and neuroprogression produced by oxidative stress in euthymic bipolar patients with different onset disease times.

Bipolar disorder (BD) is associated with systemic toxicity, represented by changes in biomarkers associated with mood episodes, leading to neurological damage, which may reflect cognitive functions and functionality and the progression of the disease. We aimed to analyze the effect of four biomarkers, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and thiobarbituric acid reactive substances (TBA-RS), related to oxidative stress in BD and to correlate them with cognitive functions and functionality. We studied 50 bipolar types I/II patients in the euthymic phase, which was divided into two subgroups with 25 patients each (≤ 3 years and ≥ 10 years of diagnosis, from the first episode of mania) and 25 control patients. To analyze frontal cognitive functions and functionality, we used the Frontal Assessment Battery (FAB) and Functioning Assessment Short Test (FAST) tests, respectively. The scores of the FAST and FAB tests showed an increase and decrease respectively, in both bipolar groups, when compared to the control group, demonstrating impairment in cognitive functions and functionality since the disease onset. In addition, changes occurred in all six domains of the FAST test, and in four domains of the FAB test in bipolar patients when compared to the control group. Regarding oxidative stress biomarkers, we did not find changes in SOD and GSH-Px activities; however, a significant increase in CAT activity and lipid peroxidation was observed in both groups, although the patients were euthymic and medicated. These results allow us to raise the hypothesis that since the beginning of the disease, the euthymic bipolar patient has presented a level of oxidative stress, which gets worse with the evolution of the disease, promoting impairments in the frontal cognitive functions and functionality gradually.

D-Galactose Causes Motor Coordination Impairment, and Histological and Biochemical Changes in the Cerebellum of Rats.

Classical galactosemia is an inborn error of carbohydrate metabolism in which patients accumulate high concentration of galactose in the brain. The most common treatment is a galactose-restricted diet. However, even treated patients develop several complications. One of the most common symptoms is motor coordination impairment, including affected gait, balance, and speech, as well as tremor and ataxia. In the present study, we investigated the effects of intracerebroventricular galactose administration on motor coordination, as well as on histological and biochemical parameters in cerebellum of adult rats. Wistar rats received 5 µL of galactose (4 mM) or saline by intracerebroventricular injection. The animals performed the beam walking test at 1 and 24 h after galactose administration. Histological and biochemical parameters were performed 24 h after the injections. The results showed motor coordination impairment at 24 h after galactose injection. Galactose also decreased the number of cells in the molecular and granular layers of the cerebellum. The immunohistochemistry results suggest that the cell types lost by galactose are neurons and astrocytes in the spinocerebellum and neurons in the cerebrocerebellum. Galactose increased active caspase-3 immunocontent and acetylcholinesterase activity, decreased acetylcholinesterase immunocontent, glutathione, and BDNF levels, as well as caused protein and DNA damage. Our results suggest that galactose induces histological and biochemical changes in cerebellum, which can be associated with motor coordination impairment.

Effects of aerobic exercise training on oxidative stress in the skeletal muscles of obese rats / Efeitos do treinamento aeróbico sobre o estresse oxidativo em músculos esqueléticos de ratos obesos / Efectos del entrenamiento aeróbico sobre el estrés oxidativo en músculos esqueléticos de ratones obesos

ABSTRACT Introduction Obesity is a complex and multifactorial metabolic disorder characterized by the accumulation of body fat; physical exercise increases energy expenditure and promotes a reparative effect through modulation of endogenous antioxidant defenses. Objective To evaluate the effects of the high-fat diet (HFD) on oxidative stress parameters in skeletal muscles of rats using aerobic exercise training protocols (AETP), moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). Methods The study was quantitative and experimental. Animals received 8 weeks of HFD or normal diet (ND), followed by 9 weeks of HFD or ND and the two AETPs. Results HFD did not alter the formation of thiobarbituric acid reactive substances (TBA-RS), total sulfhydryl and protein carbonyl content in the soleus and plantaris muscles; in contrast, the protocols caused a decrease in TBA-RS levels in the plantaris muscle and increased the sulfhydryl content in the soleus muscle, while MICT increased the sulfhydryl content in the plantaris muscle and reduced protein carbonyl content in both muscles. HFD reduced SOD activity in the plantaris muscle while the MICT protocol enhanced SOD in the soleus muscle and both protocols reversed the decrease in SOD in the plantaris muscle. HFD increased CAT activity in the soleus muscle, the HIIT protocol prevented this alteration and both protocols increased CAT in the plantaris muscle. HFD reduced GSH-Px activity in both muscles, and the MICT protocol prevented this reduction in the soleus muscle, while the HIIT protocol partially prevented this decrease. The MICT protocol did not prevent the reduction of GSH-Px and the HIIT protocol partially prevented this decrease in the plantaris muscle. Conclusions HFD elicited oxidative stress in the skeletal muscle of rats, and both protocols were able to prevent most of the alterations in oxidative stress parameters caused by the HFD. Level of evidence IV; Investigation of treatment outcomes.

RESUMO Introdução Obesidade é uma desordem metabólica complexa e multifatorial, caracterizada pelo acúmulo de gordura corporal. O exercício físico tem a capacidade de aumentar o gasto energético e promover efeito reparador por meio da modulação das defesas antioxidantes endógenas. Objetivo Avaliar os efeitos da dieta hiperlipídica (DHL) sobre parâmetros de estresse oxidativo em músculos esqueléticos de ratos, por protocolos de treinamento físico aeróbico (TFA), treinamento contínuo de intensidade moderada (TCIM) e treinamento intervalo de alta intensidade (HIIT). Métodos O estudo foi quantitativo e experimental. Animais receberam 8 semanas de DHL ou dieta normal (DN), seguidas por 9 semanas de DHL ou DN e os dois TFA. Resultados A DHL não alterou a formação de substâncias reativas ao ácido tiobarbitúrico (TBA-RS), conteúdo total de sulfidrilas e de proteínas carboniladas nos músculos sóleo e plantar. Em contraste, os protocolos diminuíram TBA-RS no músculo plantar e aumentaram o conteúdo de sulfidrilas no músculo sóleo. TCIM aumentou o conteúdo de sulfidrilas no músculo plantar e reduziu o conteúdo de proteínas carboniladas em ambos os músculos. A DHL reduziu a atividade da SOD no músculo plantar; o TCIM aumentou a SOD no músculo sóleo e ambos os protocolos reverteram a diminuição da SOD no músculo plantar. A DHL aumentou a CAT no músculo sóleo, o HIIT preveniu essa alteração e ambos os protocolos aumentaram a CAT no músculo plantar. A DHL diminuiu a atividade da GSH-Px em ambos os músculos, e o TCIM preveniu esta diminuição no músculo sóleo, enquanto que o HIIT preveniu parcialmente esta diminuição. O TCIM não preveniu a redução da GSH-Px, e o HIIT preveniu parcialmente esta diminuição no músculo plantar. Conclusão A DHL causou estresse oxidativo nos músculos esqueléticos de ratos, e ambos os protocolos foram capazes de prevenir a maioria das alterações nos parâmetros de estresse oxidativo causadas pela DHL. Nível de evidência IV; Investigação dos resultados do tratamento.

RESUMEN Introducción La obesidad es un desorden metabólico complejo y multifactorial caracterizado por la acumulación de grasa corporal. El ejercicio físico tiene la capacidad de aumentar el gasto energético y promover efecto reparador por medio de la modulación de las defensas antioxidantes endógenas. Objetivos Evaluar los efectos de la dieta hiperlipídica (DHL) sobre parámetros de estrés oxidativo en los músculos esqueléticos de las ratas, por protocolos de entrenamiento físico aeróbico (TFA), entrenamiento continuo de intensidad moderada (TCIM) y entrenamiento de intervalo de alta intensidad (HIIT). Métodos El estudio fue cuantitativo y experimental. Los animales recibieron ocho semanas de DHL o dieta normal (DN), seguidas por nueve semanas de DHL o DN y los dos TFA. Resultados La DHL no alteró la formación de sustancias reactivas al ácido tiobarbitúrico (TBA-RS), contenido total de sulfhidrilos y de proteínas carboniladas en los músculos sóleo y plantar. En contraste, los protocolos disminuyeron TBA-RS en el músculo plantar y aumentaron el contenido de sulfhidrilos en el músculo sóleo. TCIM aumentó el contenido de sulfhidrilos en el músculo plantar y redujo el contenido de proteínas carboniladas en ambos músculos. La DHL redujo la actividad de la SOD en el músculo plantar, el TCIM aumentó la SOD en el músculo sóleo y ambos protocolos revirtieron la disminución de la SOD en el músculo plantar. La DHL aumentó la CAT en el músculo sóleo, el HIIT previno esa alteración y ambos protocolos aumentaron la CAT en el músculo plantar. La DHL disminuyó la actividad de GSH-Px en ambos músculos, y el TCIM previno esta disminución en el músculo sóleo, mientras que el HIIT previno parcialmente esta disminución. El TCIM no previno la reducción de la GSH-Px y el HIIT previno parcialmente esta disminución en el músculo plantar. Conclusión La DHL causó estrés oxidativo en los músculos esqueléticos de ratones y ambos protocolos fueron capaces de prevenir la mayoría de las alteraciones en los parámetros de estrés oxidativo causados por DHL. Nivel de evidencia IV; Investigación de los resultados del tratamiento.

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

ABSTRACT Membrane/lipid rafts (MLRs) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins) can disable the N-methyl-D-aspartate (NMDA) receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

Behavioral interactions of simvastatin and fluoxetine in tests of anxiety and depression.

Simvastatin inhibits 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, and is widely used to control plasma cholesterol levels and prevent cardiovascular disease. However, emerging evidence indicates that the beneficial effects of simvastatin extend to the central nervous system. The effects of simvastatin combined with fluoxetine provide an exciting and potential paradigm to decreased anxiety and depression. Thus, the present paper investigates the possibility of synergistic interactions between simvastatin and fluoxetine in models of anxiety and depression. We investigated the effects of subchronically administered simvastatin (1 or 10 mg/kg/day) combined with fluoxetine (2 or 10 mg/kg) at 24, 5, and 1 hour on adult rats before conducting behavioral tests. The results indicate that simvastatin and/or fluoxetine treatment reduces anxiety-like behaviors in the elevated plus-maze and open-field tests. Our results showed that simvastatin and/or fluoxetine induced a significant increase in the swimming activity during the forced swimming test (antidepressant effect), with a concomitant increase in climbing time in simvastatin-treated animals only (noradrenergic activation). We hypothesize that anxiolytic and antidepressant effects of simvastatin and/or fluoxetine produce their behavioral effects through similar mechanisms and provide an important foundation for future preclinical research.

Guanidinoacetate alters antioxidant defenses and butyrylcholinesterase activity in the blood of rats

Deficiency of guanidinoacetate methyltransferase, the first described creatine biosynthesis defect, leads to depletion of creatine and phosphocreatine, and accumulation of guanidinoacetate (GAA) in brain and body fluids. The present study aimed to investigate the influence of GAA on the activities of antioxidant enzymes, as well as on thiobarbituric acid-reactive substances (TBARS) and butyrylcholinesterase (BuChE) activity in the blood of rats. We also evaluated the effect of trolox (6-hydr oxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), GSH (glutathione) and L-NAME (NG-nitro-L-arginine methyl ester) on the alterations elicited by GAA. Methods: The rats were randomly divided into 8 groups: (1) control; (2) GAA (10, 30, 50, 100 mM/kg); (3) trolox (1 mM/kg) + control; (4) trolox (1 mM/kg) + GAA (100 mM/kg); (5) GSH (1 mM/kg) + control; (6) GSH (1 mM/kg) + GAA (100 mM/kg); (7) L-NAME (1 mM/kg) + control; (8) L-NAME + GAA (100 mM/kg). After the addition of compounds, erythrocytes and plasma were pre-incubated at 37°C for 1h and tested immediately. Results: GAA enhanced the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in the erythrocytes and BuChE activity. In addition, GAA enhanced TBARS levels in the plasma. Trolox, GSH and L-NAME addition prevented the majority of alterations in oxidative stress parameters and the increase of BuChE activity that were caused by GAA. Data suggest that GAA alters antioxidant defenses and induces lipid peroxidation in the blood, as well altering BuChE activity. However, in the presence of trolox, GSH and L-NAME some of these alterations in oxidative stress and BuChE activity were prevented. Conclusions: Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by GAA...