Daniela V. Bavaresco

Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of d-AMPH

Several evidences have demonstrated that oxidative stress has a central role in bipolar disorder (BD). Recently, studies have been suggested histone deacetylases (HDAC) as a possible target for new medications in treatment of mood disorders. In this study, we investigated the effects of sodium butyrate (SB, a histone deacetilase inhibitor) on oxidative stress in rats submitted to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. Locomotor activity and risk-taking behavior were assessed by open-field test and oxidative stress was measured in prefrontal cortex, amygdala, hippocampus and striatum. The results showed that SB reversed and prevented d-AMPH-induced behavioral effects. The d-AMPH administration induced oxidative damage in all brain structures analyzed. Depending on the cerebral area and technique, SB was able to reverse this impairment. The present study reinforces the need for more studies of HDAC inhibitors as possible target for new medications in treatment for BD.

Lithium and valproate modulate energy metabolism in an animal model of mania induced by methamphetamine

Studies have shown alterations in mitochondrial complexes of bipolar disorder (BD) patients. However, changes in the Krebs cycle enzymes have been little studied. The animal model of mania induced by amphetamine has been widely used for the study of bipolar mania. The aim of this study is to assess behavioral and energy metabolism changes in an animal model of mania induced by methamphetamine (m-AMPH). Wistar rats were first given m-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with lithium (Li), valproate (VPA), or saline (Sal). Locomotor behavior was assessed using the open-field task and activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase), mitochondrial respiratory chain complexes (I, II, III, and IV), and creatine kinase measured in the brain structures (prefrontal, amygdala, hippocampus, and striatum). Li and VPA reversed m-AMPH-induced hyperactivity. The administration of m-AMPH inhibited the activities of Krebs cycle enzymes and complexes of the mitochondrial respiratory chain in all analyzed structures. Li and VPA reversed m-AMPH-induced energetic metabolism dysfunction; however, the effects of Li and VPA were dependent on the brain region analyzed. From the results obtained in this study, we suggested that the decreased Krebs cycle enzymes activity induced by m-AMPH may be inhibiting mitochondrial respiratory chain complexes. Therefore, changes in the Krebs cycle enzymes may also be involved in BD.

Behavioral changes and brain energy metabolism dysfunction in rats treated with methamphetamine or dextroamphetamine.

Studies have demonstrated that AMPHs produce long-term damage to the brain dopaminergic, serotoninergic and glutamatergic regions. Prefrontal cortex, amygdala, hippocampus and striatum appear to be involved in the toxicity and behavioral changes induced by AMPHs. A single dose of AMPH causes mitochondrial dysfunction and oxidative stress in rat brain. The goal of the present study was thus to investigate the potency of two amphetamines, dextroamphetamine (d-AMPH) and methamphetamine (m-AMPH), on the behavior and energetic dysfunction in the brain of rats. d-AMPH and m-AMPH increased the crossing and rearing behaviors. The numbers of visits to the center were increased by d-AMPH and m-AMPH only at 2mg/kg. Likewise, at a high dose (2 mg/kg), the injection of m-AMPH increased the amount of sniffing. The AMPHs significantly decreased the activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase) and mitochondrial respiratory chain complexes (I-IV); nevertheless, this effect varied depending on the brain region evaluated. In summary, this study demonstrated that at high doses, m-AMPH, increased stereotyped (sniffing) behavior in rats, but d-AMPH did not. However, this study shows that d-AMPH and m-AMPH seem to have similar effects on the brains energetic metabolism.

Effects of sodium butyrate in animal models of mania and depression: implications as a new mood stabilizer.

Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.

NMDA preconditioning prevents object recognition memory impairment and increases brain viability in mice exposed to traumatic brain injury.

Recent studies have focused on the role of N-methyl-d-aspartate (NMDA) in brain injury. The present study is aimed at verifying memory, anxiety/depression parameters, and cellular viability in the brain of mice preconditioned with NMDA and subjected to the model of mild traumatic brain injury. For this purpose, male albino CF-1 mice were pre-treated with NMDA (75 mg/kg) and subjected to brain trauma, and after 24h submitted to memory tasks and anxiety and depression-like behavioral tests. The memory tests were evaluated at 1.5h, 24h, and 7 days after the training. In addition, the cellular viability was evaluated in the cerebral cortex and hippocampus 96 h after the trauma. It was observed that the cellular viability was reduced in the hippocampus of the mice subjected to trauma and the preconditioning with NMDA was able to protect this damage. All mice learnt the task in the habituation test, but in the object recognition task the mice preconditioned with NMDA were protected against impairment induced by TBI in both short and long-term memory. On the other hand, in the step-down inhibitory avoidance test, only the mice treated with NMDA showed impairment of long-term memory (7 days after training session). The evaluation of anxiety/depression behavior showed no changes after TBI. In conclusion, NMDA preconditioning induced impairment of the long-term memory; however, it was able to protect against the novel recognition memory impairment and increase the cellular survival in the hippocampus of mice exposed to traumatic brain injury.

Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain

OBJECTIVE To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. METHOD Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. RESULTS Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. CONCLUSIONS Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD.

Effects of tamoxifen on tricarboxylic acid cycle enzymes in the brain of rats submitted to an animal model of mania induced by amphetamine

The neurobiological basis of bipolar disorder (BD) remains unknown; nevertheless, mitochondrial dysfunction has been identified in this disorder. Inactivation of any step in the tricarboxylic acid (TCA) cycle can impair mitochondrial ATP production. There is recent evidence indicating that PKC is an important therapeutic target for bipolar disorder. Therefore, we evaluated the effects of tamoxifen (TMX--a PKC inhibitor) on the activities of enzymes in the TCA cycle of rat brains subjected to an animal model of mania induced by amphetamine. In the reversal treatment, Wistar rats were first treated with d-AMPH or saliratsne (Sal) for 14 days. Thereafter, between days 8 and 14, the rats were administered TMX or Sal. The citrate synthase, succinate dehydrogenase, and malate dehydrogenase were evaluated in the frontal cortex, hippocampus, and striatum. The d-AMPH administration inhibited TCA cycle enzymes activity in all analyzed structures, and TMX reversed d-AMPH-induced dysfunction. In addition, we observed a negative correlation between d-AMPH-induced hyperactivity and the activity of these enzymes in the rats brain. These findings suggested that TCA cycle enzymes inhibition can be an important link for the mitochondrial dysfunction seen in BD, and TMX exert protective effects against the d-AMPH-induced TCA cycle enzymes dysfunction.

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes

The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.

Association between Major Depression and Type 2 Diabetes Mellitus: a Meta-Analysis and Meta-Regression of Observational Studies

The purpose of this review was to identify the prevalence of major depression in individuals with type 2 diabetes by means of a systematic review and meta-analysis. An electronic search was conducted for relevant studies published from January 1988 to December 2014. Cross-sectional and case-control studies in adults that evaluated the prevalence of major depression in individuals with type 2 Diabetes Mellitus were included. Meta-regression and sensitivity analyses were used to identify the sources of heterogeneity. Publication bias was assessed using a funnel plot and Egger’s test. After the selection process, 18 cross-sectional and four case-control studies were included in the meta-analysis. In total, the occurrence of major depression was investigated in 5554 patients with diabetes mellitus type 2. The prevalence of major depression varied from 6.67% (95% CI: 4.54% - 9.38%) to 55.38% (95% CI: 42.53% - 67.73%), with an overall average of 21.13% (95% CI: 15.80% -27.66%). In American continents, the prevalence was 20.83% (95% CI: 13.12% -31.43%; I²=96.8%), and in Europe it was 18.00% (95% CI: 8.58% -33.91%; I²=93.8%). Both were lower than the rate in Asia, which was 23.49% (95% CI: 15.63% -33.74%; I²=90.8%). Meta-regression analysis found no evidence that the analyzed cofactors represented the cause of the heterogeneity seen. The approximately symmetrical distribution of the points in Funnel Plot suggests an absence of publication bias that was confirmed by Eggers test (p=0.2345). Based on the data collected, we can infer that the prevalence of major depression in individuals with type 2 diabetes was high, independent of geographic location.