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Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.

Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitroprotocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

Recent studies have suggested that mitochondrial dysfunction and dysregulated neuroinflammatory pathways are involved in the pathophysiology of major depressive disorder (MDD). Here, we aimed to assess the differences in markers of mitochondrial dynamics, mitophagy, general autophagy, and apoptosis in peripheral blood mononuclear cells (PBMCs) of MDD patients (n= 77) and healthy controls (HCs, n= 24). Moreover, we studied inflammation engagement as a moderator of mitochondria dysfunctions on the severity of depressive symptoms. We found increased levels of Mfn-2 (p< 0.001), short Opa-1 (S-Opa-1) (p < 0.001) and Fis-1 (p< 0.001) in MDD patients, suggesting an increase in the mitochondrial fragmentation. We also found that MDD patients had higher levels of Pink-1 (p< 0.001), p62/SQSTM1 (p< 0.001), LC3B (p= 0.002), and caspase-3 active (p= 0.001), and lower levels of parkin (p< 0.001) compared with HCs. Moreover, we showed that that MDD patients with higher CRP levels had higher levels of Mfn-2 (p= 0.001) and LC3B (p= 0.002) when compared with MDD patients with low CRP. Another notable finding was that the severity of depressive symptoms in MDD is associated with changes in protein levels in pathways related to mitochondrial dynamics and mitophagy, and can be dependent on the inflammatory status. Overall, our study demonstrated that a disruption in the mitochondrial dynamics network could initiate a cascade of abnormal changes relevant to the critical pathological changes during the course of MDD and lead to poor outcomes.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges’ gwith 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Bipolar disorder (BD) is a chronic affective disorder with extreme mood swings that include mania or hypomania and depression. Though the exact mechanism of BD is unknown, neuroinflammation is one of the numerous investigated etiopathophysiological causes of BD. This article presents a systematic review of the data regarding brain inflammation evaluating microglia, astrocytes, cytokines, chemokines, adhesion molecules, and other inflammatory markers in postmortem BD brain samples. This systematic review was performed according to PRISMA recommendations, and relevant studies were identified by searching the PubMed/MEDLINE, PsycINFO, EMBASE, LILACS, IBECS, and Web of Science databases for peer-reviewed journal articles published by March 2019. Quality of included studies appraised using the QUADAS-2 tool. Among the 1814 articles included in the primary screening, 51 articles measured inflammatory markers in postmortem BD brain samples. A number of studies have shown evidence of inflammation in BD postmortem brain samples. However, an absolute statement cannot be concluded whether neuroinflammation is present in BD due to the large number of studies did not evaluate the presence of infiltrating peripheral immune cells in the central nervous system (CNS) parenchyma, cytokines levels, and microglia activation in the same postmortem brain sample. For example, out of 15 studies that evaluated microglia cells markers, 8 studies found no effect of BD on these cells. Similarly, 17 out of 51 studies evaluating astrocytes markers, 9 studies did not find any effect of BD on astrocyte cells, whereas 8 studies found a decrease and 2 studies presented both increase and decrease in different brain regions. In addition, multiple factors account for the variability across the studies, including postmortem interval, brain area studied, age at diagnosis, undergoing treatment, and others. Future analyses should rectify these potential sources of heterogeneity and reach a consensus regarding the inflammatory markers in postmortem BD brain samples.

Around 300 million individuals are affected by major depressive disorder (MDD) in the world. Despite this high number of affected individuals, more than 50% of patients do not respond to antidepressants approved to treat MDD. Patients with MDD that do not respond to 2 or more first-line antidepressant treatments are considered to have treatment-resistant depression (TRD). Animal models of depression are important tools to better understand the pathophysiology of MDD as well as to help in the development of novel and fast antidepressants for TRD patients. This review will emphasize some discovery strategies for TRD from studies on animal models, including, antagonists of N-methyl-D-aspartate (NMDA) receptor (ketamine and memantine), electroconvulsive therapy (ECT), lithium, minocycline, quetiapine, and deep brain stimulation. Animal models of depression are not sufficient to represent all the traits of TRD, but they greatly aid in understanding the mechanism by which therapies that work for TRD exert antidepressant effects. Interestingly, these innovative therapies have mechanisms of action different from those of classic antidepressants. These effects are mainly related to the regulation of neurotransmitter activity, including general glutamate and increased connectivity, synaptic capacity, and neuroplasticity.

Bipolar disorder (BD) is a chronic, debilitating illness with a global prevalence of up to 4.8%. The importance of understanding how dysfunctional mitochondria and mitophagy contribute to cell survival and death in BD is becoming increasingly apparent. Therefore, the purpose of this study was to evaluate the mitophagic pathway and NLRP3 inflammasome activation in peripheral blood mononuclear cells (PBMCs) of patients with BD and healthy individuals. Since 18-kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function and since TSPO itself impairs cellular mitophagy, we also investigated the changes in the TSPO-related pathway. Our results showed that patients with BD had lower levels of Parkin, p62/SQSTM1 and LC3A and an upregulation of TSPO pathway proteins (TSPO and VDAC), both in terms of mRNA and protein levels. Additionally, we found a negative correlation between mitophagy-related proteins and TSPO levels, while VDAC correlated negatively with p62/SQSTM1 and LC3 protein levels. Moreover, we found that the gene expression levels of the NLRP3-related proteins NLRP3, ASC, and pro-casp1 were upregulated in BD patients, followed by an increase in caspase-1 activity as well as IL-1β and IL-18 levels. As expected, there was a strong positive correlation between NLRP3-related inflammasome activation and TSPO-related proteins. The data reported here suggest that TSPO-VDAC complex upregulation in BD patients, the simultaneous downregulation of mitophagic proteins and NLRP3 inflammasome activation could lead to an accumulation of dysfunctional mitochondria, resulting in inflammation and apoptosis. In summary, the findings of this study provide novel evidence that mitochondrial dysfunction measured in peripheral blood is associated with BD.

Previous studies demonstrated significant improvement in mean pain scores and quality of life (QOL) scales in patients with chronic pain who underwent spinal cord stimulation (SCS). However, the number of individuals who experience relevant improvements in QOL, termed the meaningful clinical improvement (MCI), is not known. The present study investigated changes in pain measurements based on MCI after SCS. Thirty‐four patients with chronic intractable pain completed scales of pain (visual analogue scale [VAS]), QOL (SF‐36), and psychological dimensions during a 22‐month follow‐up period (mean). Patient‐centered MCI of the VAS and SF‐36 domain scores were determined based on the MacNab criteria of surgical global effectiveness. Independent presurgical predictors for MCI in the VAS and SF‐36 domains were analyzed using multiple binary logistic regression. There was significant improvement of pain and QOL after the SCS (p< 0.00001). Twenty‐three patients (67.6%) reached an MCI of pain, and 16 (47.7%)–23 (67.7%) reported an MCI of QOL. Predictors of MCI included ≥80% paresthesia coverage of the painful area, lower levels of anxiety and catastrophizing symptoms, shorter pain duration, female gender and no use of opioids before surgery. MCI of pain and QOL was observed in 50%–70% of patients with chronic pain after SCS. The identification of determinants for MCI is a challenge to improve the accuracy of prognostic models in SCS for patients with chronic pain. Our results, if confirmed in other populations with a larger sample size, have implications for patients with chronic pain who are candidates for SCS treatment.

•Venlafaxine and bupropion alone induced deficits in learning phase of RAM.•Paroxetine alone impairs short- and long-term recall in RAM.•Bupropion alone and combined with paroxetine impairs short-term recall in RAM.•Venlafaxine and bupropion alone impairs the short- and long term-recall in PAT.•Venlafaxine and bupropion in combination produce no significant effect in PAT.

Background: The use of antidepressants in combination is common practice following non-response to single antidepressant agents. Nevertheless, the scientific literature lacks preclinical studies regarding the combined administration of antidepressants across multiple behavioral measures including, but not limited to, cognition. Hence, we aimed to determine the effects of paroxetine (PAR), venlafaxine (VEN) and bupropion (BUP) alone or combined (PAR + BUP or VEN + BUP) on spatial and affective memory tasks to advance the knowledge about the combined use of antidepressants in cognition. Methods: Adult rats received daily injections (15 days) of PAR (20 mg/kg, ip), VEN (20 mg/kg, ip), BUP (20 mg/kg, ip) alone or combined and were submitted to behavioral measures of spatial memory (radial-arm maze — RAM), aversive memory (passive avoidance — PA), open field (OF) and forced swimming (FST) tests. Results: In the RAM, VEN or VEN + BUP impaired learning, while short-term memory (STM) was impaired by PAR, BUP and their combination. VEN + BUP improved STM as compared to BUP. PAR impaired long-term memory (LTM). VEN or BUP alone impaired STM and long-term fear memory, whilst PAR + BUP or VEN + BUP did not induce significant alterations. Conclusions: The effects of VEN, PAR or BUP alone and in combination on measures of memory are variable and vary as a function of the pharmacodynamics profile of each drug as well as the specific memory paradigm.

ObjectiveEvidence suggests that skin picking disorder (SPD) could be a prevalent condition associated with comorbidity and psychosocial dysfunction. However, just a few studies have assessed the prevalence and correlates of SPD in samples from low- and middle-income countries. In addition, the impact of SPD on quality of life (QoL) dimension after multivariable adjustment to potential confounders remains unclear.MethodsData were obtained from a Brazilian anonymous Web-based research platform. Participants provided sociodemographic data and completed the modified Skin Picking–Stanford questionnaire, the Hypomania Checklist (HCL-32), the Patient Health Questionnaire-9 (PHQ-9), the Fagerström Test for Nicotine Dependence, Alcohol Use Disorder Identification Test (AUDIT), Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report–short form, and the World Health Organization quality of life abbreviated scale (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models.ResultsFor our survey, 7639 participants took part (71.3% females; age: 27.2±7.9 years). The prevalence of SPD was 3.4% (95% CI: 3.0–3.8%), with a female preponderance (P<0.001). In addition, SPD was associated with a positive screen for a major depressive episode, nicotine dependence, and alcohol dependence, as well as suicidal ideation. Physical and psychological QoL was significantly more impaired in participants with SPD compared to those without SPD, even after adjustment for comorbidity.ConclusionsIn this large sample, SPD was a prevalent condition associated with co-occurring depression, nicotine, and alcohol dependence. In addition, SPD was independently associated with impaired physical and psychological QoL. Public health efforts toward the early recognition and treatment of SPD are warranted.

Several studies have suggested a pathophysiological role of blood cell apoptosis in major depressive disorder (MDD). The aim of this study was to evaluate mRNA expression levels of Bcl‐2, Bax, and Fas in peripheral blood mononuclear cells (PBMCs) of MDD patients with a high risk for suicide relative to those without a high risk for suicide as well as healthy subjects. The mRNA expression of Bcl‐2, Bax, and Fas as well as the Bcl‐2/Bax ratio was examined in the PBMCs of 30 MDD patients with a high risk for suicide, 30 MDD patients without a high risk for suicide, and 30 healthy controls. The mRNA expression of target genes was measured using real‐time quantitative Polymerase Chain Reaction (PCR). FAS mRNA expression was significantly increased, and Bcl‐2 mRNA expression and the Bcl‐2/Bax expression ratio were significantly decreased, in the PBMCs of MDD patients with or without a high risk for suicide attempts compared to healthy controls (p< .001). However, Bax mRNA expression was significantly increased only in MDD patients with a high risk for suicide. Moreover, MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl‐2 and Bcl‐2/Bax ratio when compared to patients without risk for suicide (p< .001). Our findings may support the role of both internal and external apoptotic pathways in the interplay between the immune system and depressive symptoms, especially in patients with a high risk for suicide.

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.

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.

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 (1.25 mg/kg), quetiapine (5 mg/kg), and lamotrigine (5.0 mg/kg) alone or in combination with ketamine (5.0 mg/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.

This study was designed to investigate the effects of treatment with the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX) in intracellular pathways in the brain of diabetic rats. To conduct this study we induced diabetes in Wistar rats with a single injection of alloxan, and afterwards rats were treated with NAC or DFX for 14 days. Following treatment completion, the immunocontent of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase-38 (MAPK38), brain-derived neurotrophic factor (BDNF), and protein kinases A and C (PKA and PKC) were determined in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). DFX treatment increased JNK content in the PFC and NAc of diabetic rats. In the amygdala, JNK was increased in diabetics treated with saline or NAC. MAPK38 was decreased in the PFC of control and in diabetic rats treated with NAC or DFX; and in the NAc in all groups. PKA was decreased in the PFC with DFX treatment. In the amygdala, PKA content was increased in diabetic rats treated with either saline or NAC, compared to controls; and it was decreased in either NAC or DFX-treated groups, compared to saline-treated diabetic animals. In the NAc, PKA was increased in NAC-treated diabetic rats. PKC was increased in the amygdala of NAC-treated diabetic rats. In the PFC, the BDNF levels were decreased following treatment with DFX in diabetic rats. In the hippocampus of diabetic rats the BDNF levels were decreased. However, treatment with DFX reversed this effect. In the amygdala the BDNF increased with DFX in non-diabetic rats. In the NAc DFX treatment increased the BDNF levels in diabetic rats. In conclusion, both diabetes and treatment with antioxidants were able to alter intracellular pathways involved in the regulation of cell survival in a brain area and treatment-dependent fashion.

ABSTRACTIntroduction: Development of xenobiotics that cross the blood-brain barrier in therapeutically-relevant quantities is an expensive and time-consuming undertaking. However, central nervous system diseases are an under-addressed cause of high mortality and morbidity, and drug development in this field is a worthwhile venture.Areas covered: We aim to familiarize the reader with available methodologies for studying drug transport into the brain. Current understanding of the blood-brain barrier structure has been well-described in other manuscripts, and first we briefly review the path that xenobiotics take through the brain – from bloodstream, to endothelial cells of the blood-brain barrier, to interstitial space, to brain parenchymal cells, and then to an exit point from the central nervous system. The second half of the review discusses research tools available to determine if xenobiotics are making the journey through the brain successfully and offers commentary on the translational utility of each methodology.Expert opinion: Theoretically, non-human mammalian and human blood-brain barriers are similar in composition; however, some findings demonstrate important differences across species. Translational methodologies may provide more reliable information about how a drug may act across species. The recent finding of lymphatic vessels within the central nervous system may provide new tools and strategies for drug delivery to the brain.

Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, this study evaluated the effects of the administration of ketamine on the phosphorylation of TrKB and CREB, and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc) rats, after the inhibition of MAPK pathway (PD184161).

Background: Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, this study evaluated the effects of the administration of ketamine on the phosphorylation of TrKB and CREB, and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc) rats, after the inhibition of MAPK pathway (PD184161). Methods: Male adult Wistar rats were submitted to a surgical procedure to receive a single dose of a pharmacological inhibitor of MAPK (PD184161) at a dose of (0.1 µg/µl) or vehicle. Then, they were divided: 1) vehicle + saline; 2) inhibitor PD184161 + saline; 3) vehicle + ketamine 15 mg/kg; and 4) inhibitor PD184161 + ketamine 15 mg/kg. Results: MEK inhibitor and ketamine increased the phosphorylation of the transcription factor cAMP response element-binding protein (pCREB) and neurotrophic factor/tropomyosin related kinase B receptor (pTrKB) in the PFC, and decreased pCREB in the hippocampus. The MEK inhibitor abolished ketamine’s effects in the hippocampus. In the amygdala, pCREB was decreased, and pTrKB was increased after MEK inhibitor plus ketamine. Ketamine increased the thiobarbituric acid reactive species (TBARS) in the PFC, hippocampus, amygdala, and NAc; MEK inhibitor antagonized these effects. The carbonyl was increased in the PFC by both ketamine and MEK inhibitor, but inhibitor infusion plus ketamine administration reduced this effect. In the amygdala, MEK inhibitor increased carbonyl. Conclusion: Ketamine’s effects on pCREB, pTrKB, and oxidative stress are mediated, at least in part, by a mechanism dependent of MAPK signaling inhibition.

Studies investigating inflammatory markers in post-traumatic stress disorder (PTSD) have yielded mixed results. The aim of our study was to compare concentrations of inflammatory markers in patients with PTSD compared with healthy controls.

Methylphenidate (MPH) is the drug of choice for pharmacological treatment of attention deficit hyperactivity disorder. Studies have pointed to the role of glucose and lactate as well as in the action mechanisms of drugs used to treat these neuropsychiatric diseases. Thus, this study aims to evaluate the effects of MPH administration on lactate release and glucose uptake in the brains of young and adult rats.

Background: Methylphenidate (MPH) is the drug of choice for pharmacological treatment of attention deficit hyperactivity disorder. Studies have pointed to the role of glucose and lactate as well as in the action mechanisms of drugs used to treat these neuropsychiatric diseases. Thus, this study aims to evaluate the effects of MPH administration on lactate release and glucose uptake in the brains of young and adult rats. Methods: MPH (1.0, 2.0 and 10.0 mg/kg) or saline was injected in young and adult Wistar male rats either acutely (once) or chronically (once daily for 28 days). Then, the levels of lactate release and glucose uptake were assessed in the prefrontal cortex, hippocampus, striatum, cerebellum and cerebral cortex. Results: Chronic MPH treatment increased glucose uptake at the dose of 10.0 mg/kg in the prefrontal cortex and striatum, and at the dose of 2.0 mg/kg in the cerebral cortex of young rats. In adult rats, an increase in glucose uptake was observed after acute administration of MPH at the dose of 10.0 mg/kg in the prefrontal cortex. After chronic treatment, there was an increase in glucose uptake with MPH doses of 2.0 and 10.0 mg/kg in the prefrontal cortex, and at an MPH dose of 2.0 mg/kg in the striatum of adult rats. The lactate release did not change with either acute or chronic treatments in young or adult rats. Conclusions: These findings indicate that MPH increases glucose consumption in the brain, and that these changes are dependent on age and posology.

•Stress and anxiety are related with anxiety DNA damage and glutamatergic alteration.•Anxious phenotype plus stress may induce a more pronounced DNA damage.•Anxious and stress induced alteration on glutamatergic neurotransmission.

The free radical theory of aging has been receiving a lot of attention in the past years. The aim of this study was to examine the correlation between oxidative damage, antioxidant enzyme activities and plasma antioxidant potential with clinical parameters in elderly people. Elderly subjects over 80 years old were included in the study. Clinical data were collected based on the Cumulative Illness Rating Scale (n= 132). In addition, blood samples were collected to determine biochemical and oxidative stress. The results showed that the mean age of the participants was 85.1 ± 4.0 years old. Diabetic patients presented higher plasma protein carbonyl levels when compared with non-diabetic, and plasma levels of thiobarbituric acid-reactive substances were correlated to serum triglyceride and LDL fraction. In contrast, a lower plasma total antioxidant capacity presented a relation with the presence of diabetes and arterial hypertension. In addition, healthy elderly subjects presented a higher plasma total antioxidant capacity. Thus, it seemed that plasma antioxidant potential is a better predictor of successful aging in the elderly than oxidative damage parameters or plasma antioxidant enzyme activities.

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.

Oxidative damage and inflammation occur early in the brain after sepsis and are resolved when long-term cognitive impairment occurs. There is no information of a direct relation between acute levels of brain inflammation and oxidative damage and long-term cognitive deficits. We hypothesized that higher levels of early oxidative damage and inflammation are followed by long-term cognitive deficits, and this is related to a decrease in the levels of brain-derived neurotropic factor (BDNF). Wistar rats were subjected to sham operation or cecal ligation and perforation and the cerebrospinal fluid (CSF) was obtained 6 and 24 h after the determination of thiobarbituric acid–reactive species, interleukin 1 (IL-1), IL-10, and tumor necrosis factor (TNF-). Animals were followed until 30 days after surgery and were subjected to the step-down inhibitory avoidance (IA) task, and the hippocampus levels of BDNF were determined. At 6 h, higher CSF levels of thiobarbituric acid–reactive species and TNF- were observed in septic animals that had a better performance in the IA task and presented higher BDNF levels in the hippocampus. At 24 h, higher CSF levels of IL-1 and TNF- were observed in septic animals that had a worse performance in the IA task, and this was associated with lower BDNF levels. The persistence of brain inflammation during the acute phase of sepsis is associated with long-term hippocampus levels of BDNF and memory impairment in sepsis survivors.

The aim of this study is to investigate the effects of pregabalin on the behavior of rats under the influence of ketamine, an NMDA receptor antagonist that mimics the symptoms of schizophrenia.

Olanzapine, an atypical antipsychotic drug with affinities for dopamine, serotonin, and histamine binding sites appears to be associated with substantial weight gain and metabolic alterations. The aim of this study was to evaluate weight gain and metabolic alterations in rats treated with olanzapine on a hypercaloric diet.

The aim of this study was to examine the effects of the N-methyl-D-aspartate receptor (NMDAR) channel blocker dizocilpine (MK-801) on lung injury in rats submitted to experimental sepsis induced by cecal ligation and perforation (CLP).

Abstract: Many biological properties have been attributed to ruthenium complex I (trans-[RuCl2(nic)4]) and ruthenium complex II (trans-[RuCl2 (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 μmol/kg), or ruthenium complex II (0.08, 4.5, or 13.6 μmol/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.

Abstract: It is well described that impairment of energy production has been implicated in the pathogenesis of a number of diseases. Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy (ECT) to minimize its side effects, little progress has been made in understanding its mechanism of action. In this work, our aim was to measure the activities of mitochondrial respiratory chain complexes II and IV and succinate dehydrogenase from rat brain after acute and chronic electroconvulsive shock (ECS). Our results showed that mitochondrial respiratory chain enzymes activities were increased after acute ECS in hippocampus, striatum and cortex of rats. Besides, we also demonstrated that complex II activity was increased after chronic ECS in cortex, while hippocampus and striatum were not affected. Succinate dehydrogenase, however, was inhibited after chronic ECS in striatum, activated in cortex and not affected in hippocampus. Finally, complex IV was not affected by chronic ECS in hippocampus, striatum and cortex. Our findings demonstrated that brain metabolism is altered by ECS.

Malathion is a pesticide used on a large scale and with high potential risk for human exposure. However, it is reasonable to hypothesize that while the malathion is metabolizing reactive oxygen species (ROS) can be generated and subsequently there is onset of an oxidative stress in central nervous system (CNS) structures: hippocampus, cortex, striatum and cerebellum of intoxicated rats due to mitochondrial respiratory chain disfunctions. The present study was therefore undertaken to evaluate malathion-induced lipid peroxidation (LPO), superoxide production from sub-mitochondrial particles and the activity of complexes II and IV of the mitochondrial respiratory chain. Malathion was administered in doses of 25, 50, 100 and 150 mg malathion/kg. After malathion administration LPO increased in hippocampus and striatum. This was accompanied by an increase in the formation of superoxide in submitochondrial particles in the hippocampus. Complex IV suffered significant inhibition of its activity. We could demonstrate in this study that malathion induces oxidative stress and it could be due to inactivation of mitochondrial respiratory complexes.Malathion is a pesticide used on a large scale and with high potential risk for human exposure. However, it is reasonable to hypothesize that while the malathion is metabolizing reactive oxygen species (ROS) can be generated and subsequently there is onset of an oxidative stress in central nervous system (CNS) structures: hippocampus, cortex, striatum and cerebellum of intoxicated rats due to mitochondrial respiratory chain disfunctions. The present study was therefore undertaken to evaluate malathion-induced lipid peroxidation (LPO), superoxide production from sub-mitochondrial particles and the activity of complexes II and IV of the mitochondrial respiratory chain. Malathion was administered in doses of 25, 50, 100 and 150 mg malathion/kg. After malathion administration LPO increased in hippocampus and striatum. This was accompanied by an increase in the formation of superoxide in submitochondrial particles in the hippocampus. Complex IV suffered significant inhibition of its activity. We could demonstrate in this study that malathion induces oxidative stress and it could be due to inactivation of mitochondrial respiratory complexes.

Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy to minimize side effects of this treatment, little progress has been made in understanding its mechanism of action. Creatine kinase is a crucial enzyme for brain energy homeostasis, and a decrease of its activity has been associated with neuronal death. This work was performed in order to evaluate creatine kinase activity from rat brain after acute and chronic electroconvulsive shock. Results showed an inhibition of creatine kinase activity in hippocampus, striatum and cortex, after acute and chronic electroconvulsive shock. Our findings demonstrated that creatine kinase activity is altered by electroconvulsive shock.Although several advances have occurred over the past 20 years concerning the use and administration of electroconvulsive therapy to minimize side effects of this treatment, little progress has been made in understanding its mechanism of action. Creatine kinase is a crucial enzyme for brain energy homeostasis, and a decrease of its activity has been associated with neuronal death. This work was performed in order to evaluate creatine kinase activity from rat brain after acute and chronic electroconvulsive shock. Results showed an inhibition of creatine kinase activity in hippocampus, striatum and cortex, after acute and chronic electroconvulsive shock. Our findings demonstrated that creatine kinase activity is altered by electroconvulsive shock.

Malathion is a pesticide with high potential for human exposure. However, it is possible that during the malathion metabolism, there is generation of reactive oxygen species (ROS) and malathion may produce oxidative stress in intoxicated rats. The present study was therefore undertaken to determine malathion-induced lipid peroxidation (LPO), protein carbonylation and to determine whether malathion intoxication alters the antioxidant system in brain rats. Malathion was administered intraperitoneally in the acute and chronic protocols in the doses of 25, 50, 100 and 150 mg malathion/kg. The results showed that LPO in brain increased in both protocols. The increased oxidative stress resulted in an increased in the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), observed in cortex, striatum in the acute malathion protocol and hippocampus in the chronic malathion protocol. Our results demonstrated that malathion induced oxidative stress and modulated SOD and CAT activity in selective brain regions.Malathion is a pesticide with high potential for human exposure. However, it is possible that during the malathion metabolism, there is generation of reactive oxygen species (ROS) and malathion may produce oxidative stress in intoxicated rats. The present study was therefore undertaken to determine malathion-induced lipid peroxidation (LPO), protein carbonylation and to determine whether malathion intoxication alters the antioxidant system in brain rats. Malathion was administered intraperitoneally in the acute and chronic protocols in the doses of 25, 50, 100 and 150 mg malathion/kg. The results showed that LPO in brain increased in both protocols. The increased oxidative stress resulted in an increased in the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), observed in cortex, striatum in the acute malathion protocol and hippocampus in the chronic malathion protocol. Our results demonstrated that malathion induced oxidative stress and modulated SOD and CAT activity in selective brain regions.

This work was performed in order to determine the level of oxidative damage and antioxidant enzymes activities late after acute and chronic electroconvulsive shock (ECS) in rats. We measured oxidative parameters in hippocampus, cortex, and striatum, at 45, 60, 90 and 120 days after a single or multiple ECS. We demonstrated an increase in lipid peroxidation after multiple ECS in the hippocampus and striatum. This was also the case for protein carbonyls in the single or multiple protocols. In this way, we demonstrated an increase in catalase in cortex in contrast to striatum and hippocampus, were there were decreases sometimes in chronic ECS. The superoxide dismutase activities decrease in different times after single and multiple ECS in the hippocampus. Our findings demonstrated that there is a delayed increase after ECS in oxidative damage and decrease in antioxidant enzymes activities in hippocampus and striatum.This work was performed in order to determine the level of oxidative damage and antioxidant enzymes activities late after acute and chronic electroconvulsive shock (ECS) in rats. We measured oxidative parameters in hippocampus, cortex, and striatum, at 45, 60, 90 and 120 days after a single or multiple ECS. We demonstrated an increase in lipid peroxidation after multiple ECS in the hippocampus and striatum. This was also the case for protein carbonyls in the single or multiple protocols. In this way, we demonstrated an increase in catalase in cortex in contrast to striatum and hippocampus, were there were decreases sometimes in chronic ECS. The superoxide dismutase activities decrease in different times after single and multiple ECS in the hippocampus. Our findings demonstrated that there is a delayed increase after ECS in oxidative damage and decrease in antioxidant enzymes activities in hippocampus and striatum.

Studies have demonstrated that oxidative stress is associated with amphetamine-induced neurotoxicity, but little is known about the adaptations of antioxidant enzymes in the brain after amphetamine exposure. We studied the effects of acute and chronic amphetamine administration on superoxide dismutase (SOD) and catalase (CAT) activity, in a rodent model of mania. Male Wistar rats received either a single IP injection of d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle (acute treatment). In the chronic treatment rats received a daily IP injection of either d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle for 7 days. Locomotor behavior was assessed using the open field test. SOD and CAT activities were measured in the prefrontal cortex, hippocampus, and striatum. Acute and to a greater extent chronic amphetamine treatment increased locomotor behavior and affected SOD and CAT activities in the prefrontal cortex, hippocampus and striatum. Our findings suggest that amphetamine exposure is associated with an imbalance between SOD and CAT activity in the prefrontal cortex, hippocampus and striatum.Studies have demonstrated that oxidative stress is associated with amphetamine-induced neurotoxicity, but little is known about the adaptations of antioxidant enzymes in the brain after amphetamine exposure. We studied the effects of acute and chronic amphetamine administration on superoxide dismutase (SOD) and catalase (CAT) activity, in a rodent model of mania. Male Wistar rats received either a single IP injection of d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle (acute treatment). In the chronic treatment rats received a daily IP injection of either d-amphetamine (1 mg/kg, 2 mg/kg, or 4 mg/kg) or vehicle for 7 days. Locomotor behavior was assessed using the open field test. SOD and CAT activities were measured in the prefrontal cortex, hippocampus, and striatum. Acute and to a greater extent chronic amphetamine treatment increased locomotor behavior and affected SOD and CAT activities in the prefrontal cortex, hippocampus and striatum. Our findings suggest that amphetamine exposure is associated with an imbalance between SOD and CAT activity in the prefrontal cortex, hippocampus and striatum.

Adult male Wistar rats were given either a single training trial or one training trial per day during 3 days followed by a retention test trial in an inhibitory avoidance (IA) task. In animals given a single training trial, pretraining, but not pretest bilateral infusion of the NMDA glutamate receptor antagonist d,l-2-amino-5-phosphonopentanoic acid (AP5) (5.0 μg) into the CA1 hippocampal area blocked IA retention. In animals given three training trials, infusions of AP5 given prior to each of the three training trials severely impaired, but did not block retention. The results indicate that NMDA receptors in the hippocampus are involved in the formation, but not in expression, of aversive memory. In addition, rats given repeated training were able to show a mild improvement of performance across training trials, possibly through mechanisms that do not depend on NMDA receptor activation in the dorsal hippocampus.Adult male Wistar rats were given either a single training trial or one training trial per day during 3 days followed by a retention test trial in an inhibitory avoidance (IA) task. In animals given a single training trial, pretraining, but not pretest bilateral infusion of the NMDA glutamate receptor antagonist d,l-2-amino-5-phosphonopentanoic acid (AP5) (5.0 μg) into the CA1 hippocampal area blocked IA retention. In animals given three training trials, infusions of AP5 given prior to each of the three training trials severely impaired, but did not block retention. The results indicate that NMDA receptors in the hippocampus are involved in the formation, but not in expression, of aversive memory. In addition, rats given repeated training were able to show a mild improvement of performance across training trials, possibly through mechanisms that do not depend on NMDA receptor activation in the dorsal hippocampus.

Serotonin (5-HT) and noradrenaline (NA) are involved in both pathogenesis and recovery from depression and anxiety. We examined the effects of acute and chronic treatment with milnacipran, a serotonin/noradrenaline reuptake inhibitors (SNRIs) antidepressant, on anxiety and memory retention in rats. Male Wistar rats received acute or chronic administration of milnacipran (12.5, 25 or 50 mg/kg) or saline (control group). The animals were separately submitted to elevated plus-maze, inhibitory avoidance and open-field tasks 1 h after injection, in the acute group, or 23 h after last injection, in the chronic group. Our results showed an anxiolytic-like effect after chronic administration of milnacipran at doses of 25 and 50 mg/kg. The treatment does not interfere in memory retention and habituation to a novel environment at any doses studied. These findings support that milnacipran, an established SNRIs antidepressant, can also be useful in the treatment of anxiety disorders.Serotonin (5-HT) and noradrenaline (NA) are involved in both pathogenesis and recovery from depression and anxiety. We examined the effects of acute and chronic treatment with milnacipran, a serotonin/noradrenaline reuptake inhibitors (SNRIs) antidepressant, on anxiety and memory retention in rats. Male Wistar rats received acute or chronic administration of milnacipran (12.5, 25 or 50 mg/kg) or saline (control group). The animals were separately submitted to elevated plus-maze, inhibitory avoidance and open-field tasks 1 h after injection, in the acute group, or 23 h after last injection, in the chronic group. Our results showed an anxiolytic-like effect after chronic administration of milnacipran at doses of 25 and 50 mg/kg. The treatment does not interfere in memory retention and habituation to a novel environment at any doses studied. These findings support that milnacipran, an established SNRIs antidepressant, can also be useful in the treatment of anxiety disorders.

Abstract: Lipid peroxidation is one of the major outcomes of free radical-mediated injury to tissuein vivo, including the central nervous system (CNS). The aim of this study was to examine whether malathion, a commonly used organophosphorus (OP), might induce oxidative stress in cerebrospinal fluid, blood serum and brain structures in male Wistar rats. Malathion was administered intraperitoneally in the doses of 25, 50, 100 and 150 mg/kg for 28 days. Oxidative damage was determined by measuring the thiobarbituric acid reactive species (TBARS) content, as an index of lipid peroxidation. TBARS concentration in the cerebrospinal fluid (CSF) and brain structures were increased, but a decrease in TBARS concentration in serum was observed. The results of the present study suggest the usefulness of TBARS measurement as a good biomarker in the estimation of malathion-induced oxidative stress affecting CSF and brain structures.

Male Wistar rats received bilateral infusions of vehicle (VEH) or aminophosphonopentanoic acid (AP5), an N-metil-D-aspartate (NMDA) receptor antagonist, into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intrahippocampal infusion of AP5 blocked 24 h IA retention. In the second experiment, animals were preexposed to the IA training context 24 h prior to training and received an infusion of either VEH or AP5 immediately after the preexposure trial and a second infusion of VEH or AP5 immediately after IA training. AP5 did not affect retention in animals preexposed to the IA box and given VEH after preexposure, but blocked retention when given after both preexposure and training. AP5 impaired retention in rats preexposed to an environment distinct from the IA box. These results suggest that NMDA receptors in the dorsal hippocampus mediate the formation of a contextual representation of the task environment.