Antidepressant Effect of Sodium Butyrate is Accompanied by Brain Epigenetic Modulation in Rats Subjected to Early or Late Life Stress.

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Depressive symptoms and neurotrophin levels in ostomy patients / Sintomas depressivos e níveis de neurotrofina em pacientes com ostomia

ABSTRACT Objective: The aim of the present study was to investigate the depressive symptoms and changes in neurotrophins (BDNF, NGF, NT-3), and cortisol levels in serum of peripheral blood from ostomy patients compared to healthy control group. Methods: We evaluated ostomy (n = 29) and healthy control (n = 30) patients. The neurotrophin (BDNF, NGF, NT-3), and cortisol levels were assessed by ELISA in serum of peripheral blood. Depressive symptoms were defined based on the Hamilton Depression Rating Scale (HDRS), and major depression disorder was based on clinical interviews and was confirmed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Results: The results showed a significant decrease in BDNF levels and, a significant increase in NT-3 levels in serum of peripheral blood from ostomy patients when compared to healthy controls. The levels of NGF and cortisol showed no significant differences between groups. The depressive symptom evaluations by HDRS demonstrated a significant increase in ostomy patients when compared to healthy controls. The major depression disorder diagnosis by SCID-I showed no significant difference between groups. Conclusion: Our results suggest ostomy triggers significant depressive symptoms and alterations in neurotrophins levels in serum of peripheral blood samples collected from these patients.

RESUMO Objetivo: O objetivo do presente estudo foi investigar os sintomas depressivos e alterações nos níveis de neurotrofinas (BDNF, NGF, NT-3) e cortisol em soro de sangue periférico de pacientes ostomizados em comparação com grupo controle saudável. Métodos: Foram avaliados pacientes ostomizados (n = 29) e controles saudáveis (n = 30). Os níveis de neurotrofinas (BDNF, NGF, NT-3) e cortisol foram avaliados por kit ELISA em soro de sangue periférico. Os sintomas depressivos foram definidos com base na Hamilton Depression Rating Scale (HDRS), e o transtorno depressivo maior foi baseado em entrevistas clínicas e confirmado pela Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Resultados: Os resultados mostraram diminuição significativa nos níveis de BDNF e aumento significativo nos níveis de NT-3 no soro de sangue periférico de pacientes ostomizados quando comparados com controles saudáveis. Os níveis de NGF e cortisol não apresentaram diferenças significativas entre os grupos. As avaliações dos sintomas depressivos pela HDRS demonstraram aumento significativo em pacientes ostomizados quando comparados com controles saudáveis. O diagnóstico de transtorno depressivo maior pela SCID-I não mostrou diferença significativa entre os grupos. Conclusão: Nossos resultados sugerem que a ostomia desencadeia sintomas depressivos significativos e alterações nos níveis de neurotrofinas no soro de sangue periférico coletadas desses pacientes

Sodium butyrate functions as an antidepressant and improves cognition with enhanced neurotrophic expression in models of maternal deprivation and chronic mild stress.

It is known that cognitive processes, such as learning and memory, are affected in depression. Several authors have described histone deacetylase (HDAC) inhibitors as a class of drugs that improves long-term memory formation. The current study examined the effects of maternal deprivation (MD) and chronic mild stress (CMS), which have been shown as animal models of depression, and the effects of sodium butyrate (SB), a HDAC inhibitor, on recognition memory. Considering that neurotrophic factors has been pointed as a key event involved with cognition and depressive disorder, levels of neurotrophic factors (BDNF, NGF and GDNF) were also investigated. MD and CMS induced depressive-like behavior in the forced swimming test (FST) and memory impairment in the object recognition (OR) test, without altering locomotor activity of rats. In addition, SB was able to reverse the stress-induced neurotrophic factors decrease and reversed memory impairment. The results indicate that the stress both at early and later stage of life may induce cognitive impairment in animals and neurotrofic factors (BDNF, NGF and GDNF) levels decrease. SB treatment improved the recognition memory and reversed the neurotrophins levels decreased in the hippocampus of rats submitted to the MD and CMS models. Together, our results reinforce the notion that SB displays a specific antidepressant profile and improve cognition in MD and CMS rats that may be, at least in part, due to its upregulation of neurotrophic factors.

Protein kinase C and oxidative stress in an animal model of mania.

The present study aims to investigate the effects of protein kinase C using the inhibitor Tamoxifen (TMX) on oxidative stress in a rat animal model of mania induced by d-amphetamine (d-AMPH). In the reversal model, d-AMPH or saline (Sal) were administered to rats for 14 days, and between days 8-14, rats were treated with TMX or Sal. In the prevention model, rats were pretreated with TMX or Sal, and between days 8-14, d-AMPH or Sal were administrated. In both experiments locomotor activity and risk-taking behavior were assessed by open-field test and oxidative stress was measured in prefrontal, amygdala, hippocampus and striatum. The results showed that TMX reversed and prevented d- AMPH-induced behavioral effects. In addition, the d-AMPH administration induced oxidative damage in both structures tested in two models. The TMX was able to reverse and prevent this impairment, however in a way dependent of cerebral area and technique evaluated. These findings reinforce the hypothesis that PKC play an important role in the pathophysiology of BD and the need for the study of inhibitors of PKC as a possible target for treatment the BD.

Pharmacological activity of ruthenium complexes trans-[RuCl(2)(L)4] (l = nicotinic or i-nicotinic acid) on anxiety and memory in rats.

Many biological properties have been attributed to ruthenium complex I (trans-[RuCl(2)(nic)(4)]) and ruthenium complex II (trans-[RuCl(2 )(i-nic)( 4)]) including nitric oxide synthase inhibition. In this study, we evaluated pharmacological effects of these complexes on anxiety and memory formation. Memory was evaluated with inhibitory avoidance and habituation to an open-field and anxiety was tested with elevated plus-maze. Adult male Wistar rats (250 to 350 g) received intraperitoneal injections of vehicle, ruthenium complex I (45.2, 90.4, or 180.7 mumol/kg), or ruthenium complex II (0.08, 4.5, or 13.6 mumol/kg) 30 min prior open-field training or elevated plus-maze test and 30 min or 0 h after training. No effects were observed in the anxiety parameters and habituation to an open-field. The ruthenium complexes impaired memory retention compared with vehicle group in the inhibitory avoidance, as when administrated 30 min prior as immediately after training. The memory impairment induced by ruthenium complexes may be due to their nitric oxide synthase inhibition capacity.