Acute and chronic treatment with quetiapine induces antidepressant-like behavior and exerts antioxidant effects in the rat brain.

Many studies note that changes in oxidative balance are involved in the pathogenesis of major depressive disorder (MDD) and in the success of some antidepressants. Quetiapine exerts a therapeutic response and induces changes in physiological mechanisms that appear to underlie MDD. The objective of this study was to evaluate the antidepressant and antioxidant effects of quetiapine (20 mg /kg) in adult animals. Sixty minutes after an acute treatment or the last administration of chronic treatment (14 days) with quetiapine, animals were subjected to the forced swimming test (FST) to evaluate mobility parameters. Then, the hippocampus, prefrontal cortex (CPF), amygdala and nucleus accumbens (NAc) were removed for the assessment of oxidative stress parameters. Both acute and chronic treatments exerted antidepressant-like effects. Myeloperoxidase (MPO) activity was reduced in the amygdala after acute treatment and in the hippocampus, PFC and amygdala after chronic treatment. In addition, after chronic treatment, the levels of thiobarbituric reactive species (TBARS) were reduced in the amygdala and NAc, and the protein carbonyl content was reduced in the CPF. Superoxide dismutase (SOD) activity increased in the NAc after acute and chronic treatments. Catalase (CAT) activity increased in the PFC after acute treatment and in the NAc after acute and chronic treatments. The concentration of nitrite/nitrate was lower in the CPF after chronic treatment. These results corroborate the antidepressant effect of quetiapine and indicate that quetiapine exhibits an antioxidant profile, a physiological mechanism that appears be involved in the therapeutic function of quetiapine in individuals resistant to classical antidepressant treatments.

Efeitos do ruído na escola: percepção de professores do ensino infantil e fundamental I e II que atuam em escola privada no Vale do Itajaí / Effects of noise at school: perception of kindergarten and elementary school teachers I and II who work in private schools in Vale do Itajaí / Efectos del ruido en la escuela: percepción de los profesores de jardín de infancia y escuela primaria I y II que actúan en escuelas privadas del Vale do Itajaí

Introdução: a exposição ao ruído no ambiente escolar pode gerar desconforto, sendo apontada como um dos fatores relacionados às dificuldades de aprendizagem e concentração. Objetivo: definir a relação entre a exposição ao ruído e os efeitos auditivos e não auditivos na percepção de professores do ensino infantil e fundamental I e II em uma escola privada no Vale do Itajaí. Metodologia: coleta de dados com aplicação de questionário online respondido por 29 professores, contendo perguntas de múltipla escolha, com análise estatística descritiva. Resultados: 89,66% dos professores têm jornada de trabalho semanal superior a 20 horas/aula; 20% percebem a presença de ruído na escola, sendo esta de intensidade moderada; 68,97% apontaram como principal fonte de ruído os próprios alunos e 62,07% o intervalo e a quadra de esportes; 41,4% percebem prejuízos na saúde, porém desconhecem a existência de normas regulamentadoras sobre o ruído na escola; 100% relatam sintomas de estresse, ansiedade, irritabilidade e/ou insônia e 68,96% relacionam estes com a exposição ao ruído; 34,48% percebem agravos dos sintomas após as aulas; 55,17% nunca receberam informações ou participaram de atividades sobre o ruído, embora 86,21% "fazem combinados" [estabelecem regras] com os alunos para minimizar os efeitos do ruído no ambiente escolar. Conclusão: os efeitos do ruído na escola são percebidos pelos professores, principalmente no intervalo das aulas, sendo os sintomas de estresse, ansiedade, irritabilidade e/ou insônia os mais citados. (AU)

Introduction: exposure to noise in the school environment can cause discomfort, being identified as one of the factors related to learning and concentration difficulties. Objective: to define the relationship between exposure to noise and auditory and non-auditory effects on the perception of teachers of kindergarten and elementary education I and II in a private school in Vale do Itajaí. Methodology: data collection using an online questionnaire answered by 29 teachers, containing multiple choice questions, with descriptive statistical analysis. Results: 89.66% of teachers have a weekly working day of more than 20 hours/class; 20% perceive the presence of noise at school, which is of moderate intensity; 68.97% pointed to the students themselves as the main source of noise and 62.07% to recess and the sports court; 41.4% perceive health losses, but are unaware of the existence of regulatory standards regarding noise at school; 100% report symptoms of stress, anxiety, irritability and/or insomnia and 68.96% relate these to noise exposure; 34.48% notice worsening of symptoms after classes; 55.17% never received information or participated in activities about noise, although 86.21% "made arrangements" [established rules] with students to minimize the effects of noise in the school environment. Conclusion: the effects of noise at school are noticed by teachers, especially during class breaks, with symptoms of stress, anxiety, irritability and/or insomnia being the most cited. (AU)

Introducción: la exposición al ruido en el ambiente escolar puede causar malestar, identificándose como uno de los factores relacionados con las dificultades de aprendizaje y concentración. Objetivo:definir la relación entre la exposición al ruido y los efectos auditivos y no auditivos en la percepción de profesores de jardín de infantes y educación primaria I y II en una escuela privada del Vale do Itajaí. Metodología: recolección de datos mediante cuestionario en línea respondido por 29 docentes, que contiene preguntas de opción múltiple, con análisis estadístico descriptivo. Resultados: el 89,66% de los docentes tienen una jornada laboral semanal superior a 20 horas/clase; El 20% percibe la presencia de ruido en el colegio, el cual es de intensidad moderada; El 68,97% señaló a los propios alumnos como principal fuente de ruido y el 62,07% al recreo y la cancha deportiva; El 41,4% percibe pérdidas en la salud, pero desconoce la existencia de normas regulatorias en materia de ruido en la escuela; El 100% reporta síntomas de estrés, ansiedad, irritabilidad y/o insomnio y el 68,96% los relaciona con la exposición al ruido; el 34,48% notan empeoramiento de los síntomas después de clases; El 55,17% nunca recibió información ni participó en actividades sobre ruido, aunque el 86,21% "hizo arreglos" [estableció reglas] con los estudiantes para minimizar los efectos del ruido en el ambiente escolar. Conclusión: los efectos del ruido en la escuela son notados por los profesores, especialmente durante los recreos de clase, siendo los síntomas de estrés, ansiedad, irritabilidad y/o insomnio los más citados. (AU)

ω-3 and folic acid act against depressive-like behavior and oxidative damage in the brain of rats subjected to early- or late-life stress.

OBJECTIVES: To investigate the antidepressant and antioxidant effects of omega-3, folic acid and n-acetylcysteine (NAC) in rats which were subjected to early or late life stress. METHODS: Early stress was induced through maternal deprivation (MD), while late life stress was induced using the chronic mild stress (CMS) protocol. Young rats which were subjected to MD and the adult rats which were subjected to CMS were treated with omega-3 fatty acids (0.72 g/kg), NAC (20 mg/kg) or folic acid (50 mg/kg) once/day, for a period of 20 days. Then, the animals' immobility times were evaluated using the forced swimming test. Oxidative stress parameters were evaluated in the brain. RESULTS: Depressive-like behavior induced by CMS was prevented by NAC and folic acid, and depressive-like behavior induced by MD was prevented by NAC, folic acid and omega-3. NAC, folic acid and omega-3 were able to exert antioxidant effects in the brain of rats subjected to CMS or MD. These preventive treatments decreased the levels of protein carbonylation and lipid peroxidation, and also decreased the concentrations of nitrite/nitrate and reduced the activity of myeloperoxidase activity in the rat brain which was induced by CMS or MD. NAC, folic acid and omega-3 increased superoxide dismutase and catalase activities in the rat brain subjected to early or late life stress. CONCLUSIONS: NAC, omega-3 and folic acid may present interesting lines of treatment based on their antioxidant properties, which cause an inhibition of behavioral and brain changes that occur from stressful life events.

Acute treatment with ketamine and chronic treatment with minocycline exert antidepressant-like effects and antioxidant properties in rats subjected different stressful events.

Despite decades of research, the fundamental neurochemical and molecular mechanisms underlying the major depressive disorder (MDD) are still poorly understood, and current antidepressant treatments have limited clinical efficacy. In clinical conditions, the rapprochement between the disease and the corrective actions of drugs in laboratory animals is essential for developing effective therapies. Thus, the aim of this study was to evaluate the antidepressant effects of ketamine (N-metil-d-asparte (NMDA) receptor antagonist), minocycline (tetracycline antibiotic), and amitriptyline (classical antidepressant), on behavior and oxidative stress parameters in animals submitted to the chronic mild stress (CMS) and maternal deprivation protocols. For this aim, male Wistar rats were submitted to maternal deprivation or CMS. To induce maternal deprivation, Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, Wistar rats were submitted to the CMS for 40 days. To reverse the effects of stress, treatment was done intraperitoneally with a single dose of ketamine (15 mg/kg), and minocycline (25 mg/kg) and amitriptyline (10 mg/kg) by 20 days. After treatment, the animals were submitted to the forced swimming test and then analyzed oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). Treatment with ketamine, minocycline and amitriptyline were able to exert antidepressant effects in the forced swimming test. However, these antidepressant effects were dependent on the stress model by which the animals were exposed. In certain brain regions some treatment strategies had a pro-oxidant effect. Though, most of the strategies used in this study had antioxidant effects, as reported by a decrease on protein and lipid damage, nitrite/nitrate concentration and myeloperoxidase activity. In addition, an increase in the antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes activities were also evident after treatments. In conclusion, the antidepressant effects of ketamine and minocycline, in the present study, may be associated, at least in part, with its antioxidant and neuroprotective effects in animals subjected to maternal deprivation or CMS.

The impact of chronic mild stress on long-term depressive behavior in rats which have survived sepsis.

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis.

Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation.

Stress in early life has been appointed as an important phenomenon in the onset of depression and poor response to treatment with classical antidepressants. Furthermore, childhood trauma triggers epigenetic changes, which are associated with the pathophysiology of major depressive disorder (MDD). Treatment with atypical antipsychotics such as quetiapine, exerts therapeutic effect for MDD patients and induces epigenetic changes. This study aimed to analyze the effect of chronic treatment with quetiapine (20mg/kg) on depressive-like behavior of rats submitted to maternal deprivation (MD), as well as the activity of histone acetylation by the enzymes histone acetyl transferases (HAT) and deacetylases (HDAC) and DNA methylation, through DNA methyltransferase enzyme (DNMT) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and hippocampus. Maternally deprived rats had a depressive-like behavior in the forced swimming test and an increase in the HDAC and DNMT activities in the hippocampus and NAc. Treatment with quetiapine reversed depressive-like behavior and reduced the DNMT activity in the hippocampus. This is the first study to show the antidepressant-like effect of quetiapine in animals subjected to MD and a protective effect by quetiapine in reducing epigenetic changes induced by stress in early life. These results reinforce an important role of quetiapine as therapy for MDD.

Mechanism of synergistic action on behavior, oxidative stress and inflammation following co-treatment with ketamine and different antidepressant classes.

BACKGROUND: Major depressive disorder (MDD) affects many people in the world. However, around 40% of patients do not respond to any pharmacological drugs. An alternative is to use a combination of different pharmacological groups or the combination of a classical antidepressant with a substance that can potentiate its effect. Thus, this study aimed to investigate the synergistic interactions between different antidepressants, including fluoxetine, quetiapine and lamotrigine in combination with ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist. METHODS: Wistar rats were acutely treated with fluoxetine (1.25mg/kg), quetiapine (5mg/kg), and lamotrigine (5.0mg/kg) alone or in combination with ketamine (5.0mg/kg), and then subjected to behavioral tests. In addition, oxidative damage and antioxidant capacity were assessed in the rat brain, and pro-inflammatory cytokines levels were evaluated in the serum. RESULTS: It was observed a synergistic effect of ketamine in combination with fluoxetine on the immobility time in the forced swimming test, indicating an antidepressant effect. Other antidepressant did not show effects when administrated alone or joint to ketamine. The combination of ketamine with other antidepressants, particularly quetiapine, in some brain regions induced an increase in damage to lipids and proteins. However, the combination of ketamine with fluoxetine increased the antioxidant activity of superoxide dismutase, and decreased oxidative damage, thus suggesting a neuroprotective effect of the combination of these drugs. The combination of ketamine with fluoxetine or lamotrigine reduced pro-inflammatory cytokines levels. CONCLUSION: In conclusion, ketamine induced antioxidant or pro-antioxidant effects dependent of antidepressant classes or brain area.

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.

Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.