Amygdala-specific changes in Cacna1c, Nfat5, and Bdnf expression are associated with stress responsivity in mice: A possible mechanism for psychiatric disorders.

The CACNA1C gene encodes the alpha-1c subunit of the Cav1.2 calcium channel, a regulator of neuronal calcium influx involved in neurotransmitter release and synaptic plasticity. Genetic data show a role for CACNA1C in depressive symptoms underlying different psychiatric diagnoses. However, the mechanisms involved still require further exploration. This study aimed to investigate sex and region-specific changes in the Cacna1c gene and behavioral outcomes in mice exposed to chronic stress. Moreover, we evaluated the Nuclear factor of activated T-cells 5 (Nfat5) and the Brain-derived neurotrophic factor (Bdnf) as potential upstream and downstream Cacna1c targets and their correlation in stressed mice and humans with depression. Male and female Swiss mice were exposed to chronic unpredictable stress (CUS) for 21 days. Animal-integrated emotionality was assessed using the sucrose splash test, the tail suspension, the open-field test, and the elevated-plus-maze. Gene expression analysis was performed in the amygdala, prefrontal cortex, and hippocampus. Human data for in silico analysis was obtained from the Gene Expression Omnibus. CUS-induced impairment in integrated emotional regulation was observed in males. Gene expression analysis showed decreased levels of Cacna1c and Nfat5 and increased levels of Bdnf transcripts in the amygdala of stressed male mice. In contrast, there were no major changes in behavioral responses or gene expression in female mice after stress. The expression of the three genes was significantly correlated in the amygdala of mice and humans. The strong and positive correlation between Canac1c and Nfat5 suggests a potential role for this transcription factor in Canac1c expression. These changes could impact amygdala reactivity and emotional responses, making them a potential target for psychiatric intervention.

Depicting the molecular features of suicidal behavior: a review from an "omics" perspective.

Background Suicide is one of the leading global causes of death. Behavior patterns from suicide ideation to completion are complex, involving multiple risk factors. Advances in technologies and large-scale bioinformatic tools are changing how we approach biomedical problems. The "omics" field may provide new knowledge about suicidal behavior to improve identification of relevant biological pathways associated with suicidal behavior. Methods We reviewed transcriptomic, proteomic, and metabolomic studies conducted in blood and post-mortem brains from individuals who experienced suicide or suicidal behavior. Omics data were combined using systems biology in silico, aiming at identifying major biological mechanisms and key molecules associated with suicide. Results Post-mortem samples of suicide completers indicate major dysregulations in pathways associated with glial cells (astrocytes and microglia), neurotransmission (GABAergic and glutamatergic systems), neuroplasticity and cell survivor, immune responses and energy homeostasis. In the periphery, studies found alterations in molecules involved in immune responses, polyamines, lipid transport, energy homeostasis, and amino and nucleic acid metabolism. Limitations We included only exploratory, non-hypothesis-driven studies; most studies only included one brain region and whole tissue analysis, and focused on suicide completers who were white males with almost none confounding factors. Conclusions We can highlight the importance of synaptic function, especially the balance between the inhibitory and excitatory synapses, and mechanisms associated with neuroplasticity, common pathways associated with psychiatric disorders. However, some of the pathways highlighted in this review, such as transcriptional factors associated with RNA splicing, formation of cortical connections, and gliogenesis, point to mechanisms that still need to be explored.

Behavioral flexibility impacts on coping and emotional responses in male mice submitted to social defeat stress.

Behavioral flexibility permits the appropriate behavioral adjustments in response to changing environmental demands. The present study aimed to evaluate if variability in baseline flexibility can enable differences in coping strategies, changes in neuroplasticity, and behavioral outcomes in responses to chronic social defeat stress (CSDS). Male C57BL6 mice were submitted to the Morris Water Maze (MWM) using an extended protocol for reversal learning to assess. The animals were divided into low and high behavioral flexibility groups based on their performance on the last day of acquisition versus the four days of reversal learning. The CSDS was applied for ten consecutive days, and coping strategies were evaluated during the physical interaction on the first and last day of stress. A battery of behavioral tests to assess social and emotional behavior was conducted 24 h after the CSDS protocol. The complexity of prefrontal cortex (PFC) neuronal morphology was evaluated by the Golgi-Cox method. Animals with High Flexibility exhibited changes in their CSDS coping strategies, from active to passive coping, during the CSDS protocol. Low Flexibility mice had no alterations in the coping strategies during CSDS. After social stress, High Flexibility was associated with reduced social interaction with an aggressive Swiss mouse, higher latency to immobility in the tail suspension test, and reduced latency to self-care in the sucrose splash test. High Flexibility mice also displayed higher dendritic complexity on pyramidal neurons from the prelimbic and infralimbic prefrontal cortex compared to Low Flexibility mice. These results suggest That High Flexibility is associated with increased neuroplasticity in cortical areas and better emotional responses related to behavioral despair and motivation. However, exposure to CSDS reversed the beneficial effects of High Flexibility in male mice. Thus, this study suggests that baseline variability in behavioral flexibility, even in inbred strains, might be associated with differences in coping strategies, PFC morphology, and behavioral responses to social stress.

BDNF Levels According to Variations in the CACNA1C Gene: Sex-Based Disparity.

The CACNA1C gene encodes the pore-forming alpha-1c subunit of L-type voltage-gated calcium channels. The calcium influx through these channels regulates the transcription of the brain-derived neurotrophic factor (BDNF). Polymorphisms in this gene have been consistently associated with psychiatric disorders, and alterations in BDNF levels are a possible biological mechanism to explain such associations. Here, we sought to investigate the effect of the CACNA1C rs1006737 and rs4765913 polymorphisms and their haplotypes on serum BDNF concentration. We further aim to investigate the regulatory function of these SNPs and the ones linked to them. The study enrolled 641 young adults (362 women and 279 men) in a cross-sectional population-based survey. Linear regression was used to test the effects of polymorphisms and haplotypes on BDNF levels adjusted for potential confounders. Moreover, regulatory putative functional roles were assessed using in silico approach. BDNF levels were not associated with CACNA1C polymorphisms/haplotype in the total sample. When the sample was stratified by sex, checking the effect of polymorphisms on men and women separately, the A-allele of rs4765913 was associated with lower BDNF levels in women compared with the TT genotype (p = 0.010). The AA (rs1006737-rs4765913) haplotype was associated with BDNF levels in opposite directions regarding sex, with lower levels of BDNF in women (p = 0.040) compared to those without this haplotype, while with higher levels in men (p = 0.027). These findings were supported by the presence of regulatory marks only on the male fetal brain. Our results suggest that the BDNF levels regulation may be a potential mechanism underpinning the association between CACNA1C and psychiatric disorders, with a differential role in women and men.

Cross-cultural adaptation and psychometric evaluation of the Brazilian version of the Temporal Experience of Pleasure Scale (TEPS-Br).

INTRODUCTION: Anhedonia is a critical symptom of major depressive disorder that is defined as the reduced ability to experience pleasure. The Temporal Experience of Pleasure Scale (TEPS) is commonly used to measure anhedonia and has exhibited satisfactory reliability. OBJECTIVES: We aim to perform cross-cultural adaptation of a Brazilian version of the TEPS and evaluate its psychometric properties. METHOD: The cross-cultural adaptation was performed according to previously established protocols. Cronbach's alpha coefficient of internal consistency was used to establish the degree of interrelation and coherence of items. Also, we calculated the intraclass correlation coefficient to determine the stability of the scale after a proposed interval had elapsed and used exploratory factor analysis to evaluate the scale's factor structure and content validity. Principal component analysis was used to determine the factors to be retained in the factor model. RESULTS: The participants reported that the Brazilian version of the TEPS had good comprehensibility and applicability. The results revealed a statistically significant correlation between measures. The intraclass correlation coefficient calculated was significant. The Cronbach's alpha value calculated indicated that the scale's overall internal consistency was adequate. CONCLUSION: The Portuguese version of the TEPS scale proposed achieved good comprehensibility for the Brazilian population and its psychometric characteristics demonstrated good reliability and validity.

Role of heme oxygenase-1 in the antidepressant-like effect of ursolic acid in the tail suspension test.

OBJECTIVES: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties. METHODS: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex. KEY FINDINGS: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex. CONCLUSIONS: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST.

Cross-cultural adaptation and psychometric evaluation of the Brazilian version of the Temporal Experience of Pleasure Scale (TEPS-Br)

Abstract Introduction: Anhedonia is a critical symptom of major depressive disorder that is defined as the reduced ability to experience pleasure. The Temporal Experience of Pleasure Scale (TEPS) is commonly used to measure anhedonia and has exhibited satisfactory reliability. Objectives: We aim to perform cross-cultural adaptation of a Brazilian version of the TEPS and evaluate its psychometric properties. Method: The cross-cultural adaptation was performed according to previously established protocols. Cronbach's alpha coefficient of internal consistency was used to establish the degree of interrelation and coherence of items. Also, we calculated the intraclass correlation coefficient to determine the stability of the scale after a proposed interval had elapsed and used exploratory factor analysis to evaluate the scale's factor structure and content validity. Principal component analysis was used to determine the factors to be retained in the factor model. Results: The participants reported that the Brazilian version of the TEPS had good comprehensibility and applicability. The results revealed a statistically significant correlation between measures. The intraclass correlation coefficient calculated was significant. The Cronbach's alpha value calculated indicated that the scale's overall internal consistency was adequate. Conclusion: The Portuguese version of the TEPS scale proposed achieved good comprehensibility for the Brazilian population and its psychometric characteristics demonstrated good reliability and validity.

Low doses of ketamine and guanosine abrogate corticosterone-induced anxiety-related behavior, but not disturbances in the hippocampal NLRP3 inflammasome pathway.

RATIONALE: Guanosine has been shown to potentiate ketamine's antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined. OBJECTIVE: This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling. METHODS: Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments. RESULTS: Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1ß in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway. CONCLUSIONS: Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response.

Leptin polymorphism rs3828942: risk for anxiety disorders?

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary.

Glibenclamide treatment prevents depressive-like behavior and memory impairment induced by chronic unpredictable stress in female mice.

Glibenclamide is a second-generation sulfonylurea used in the treatment of Type 2 Diabetes Mellitus. The primary target of glibenclamide is ATP-sensitive potassium channels inhibition; however, other possible targets include the control of inflammation and blood-brain barrier permeability, which makes this compound potentially interesting for the management of brain-related disorders. Here, we showed that systemic treatment with glibenclamide (5 mg/kg, p.o., for 21 days) could prevent the behavioral despair and the cognitive dysfunction induced by chronic unpredictable stress (CUS) in mice. In nonhypoglycemic doses, glibenclamide attenuated the stress-induced weight loss, decreased adrenal weight, and prevented the increase in glucocorticoid receptors in the prefrontal cortex, suggesting an impact in hypothalamic-pituitary-adrenal (HPA) axis function. Additionally, we did not observe changes in Iba-1, NLRP3 and caspase-1 levels in the prefrontal cortex or hippocampus after CUS or glibenclamide treatment. Thus, this study suggests that chronic treatment with glibenclamide prevents the emotional and cognitive effects of chronic stress in female mice. On the other hand, the control of neuroinflammation and NLRP3 inflammasome pathway is not the major mechanism mediating these effects. The behavioral effects might be mediated, in part, by the normalization of glucocorticoid receptors and HPA axis.

Physical exercise prevents amyloid ß1-40-induced disturbances in NLRP3 inflammasome pathway in the hippocampus of mice.

Amyloid beta (Aß), one of the main hallmarks of Alzheimer's Disease (AD), may stimulate pattern recognition receptors (PRR) such as the NLRP3 inflammasome, inducing a pro-inflammatory state in the brain that contributes to disease development. Physical exercise can have multiple beneficial effects on brain function, including anti-inflammatory and neuroprotective roles. The objective of this study was to investigate the prophylactic effect of moderate treadmill exercise for 4 weeks on inflammatory events related to NLRP3 signaling in the hippocampus of mice after intracerebroventricular Aß1-40 administration. Our results show that Aß1-40 administration (400 pmol/mouse, i.c.v.) significantly increased the immunocontent Iba-1 (a microglial reactivity marker), NLRP3, TXNIP, and caspase-1 in the hippocampus of mice. However, physical exercise prevented the hippocampal increase in Iba-1, TXNIP, and activation of the NLRP3 inflammasome pathway caused by Aß1-40. Moreover, physical exercise per se reduced the TXNIP and caspase-1 immunocontent in the hippocampus. No alterations were observed on the immunocontent of GFAP, ASC, and IL-1ß in the hippocampus after Aß1-40 and/or physical exercise. These results reinforce the role of NLRP3 inflammasome pathway in AD and point to physical exercise as a possible non-pharmacological strategy to prevent inflammatory events triggered by Aß1-40 in mice.

Stress and signaling pathways regulating autophagy: From behavioral models to psychiatric disorders.

Autophagy is a process of degradation and recycling of cytoplasmatic components by the lysosomes. In the central nervous system (CNS), autophagy is involved in cell surveillance, neuroinflammation, and neuroplasticity. Neuropsychiatric conditions are associated with functional disturbances at molecular and cellular levels, causing significant impairments in cell homeostasis. Additionally, emerging evidence supports that dysfunctions in autophagy contribute to the pathophysiology of neurological diseases. However, the studies on autophagy in psychiatric disorders are highly heterogeneous and have several limitations, mainly to assess causality and determine the autophagy flux in animals and human samples. Besides, the role of this mechanism in non-neuronal cells in the CNS is only recently being explored. Thus, this review summarizes and discusses the changes in the autophagy pathway in animal models of psychiatric disorders and the limitations underlying the significant findings. Moreover, we compared these findings with clinical studies. Understanding the involvement of autophagy in psychiatric conditions, and the limitation of our current models may contribute to the development of more effective research approaches and possibly pharmacological therapies.

Subthreshold doses of guanosine plus ketamine elicit antidepressant-like effect in a mouse model of depression induced by corticosterone: Role of GR/NF-κB/IDO-1 signaling.

Augmentative treatment is considered the best second-option when a first-choice drug has partial limitations, particularly by allowing antidepressant dose reduction. Considering that ketamine has significant knock-on effects, this study investigated the effects of a single coadministration with subthreshold doses of ketamine plus guanosine in a corticosterone (CORT)-induced animal model of depression and the role of anti-inflammatory and antioxidant pathways. CORT administration (20 mg/kg, p.o. for 21 days) increased the immobility time in the tail suspension test (TST) and the grooming latency in the splash test (SPT), as well as reduced the total time of grooming in the SPT. These behavioral alterations were accompanied by impaired hippocampal slices viability, elevated immunocontent of nuclear factor-kappa B (NF-κB) and indoleamine-2,3-dioxygenase 1 (IDO-1), and reduced immunocontent of glucocorticoids receptor (GR), glutamate transporter (GLT-1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in the hippocampus. CORT also decreased the thioredoxin reductase activity in the hippocampus, while reduced the glutathione reductase activity and non-protein thiols levels in both hippocampus and prefrontal cortex. In addition, elevated content of malondialdehyde and protein carbonyl was also observed in the hippocampus and prefrontal cortex of CORT-treated mice. Of note, a single administration of ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) attenuated the depressive-like behavior and hippocampal slices impairments induced by CORT. The behavioral response obtained by the combined administration of these drugs was paralleled by the reestablishment of the CORT-induced molecular alterations on hippocampal GR, NF-κB, IDO-1, and GLT-1 immunocontent. Moreover, CORT-induced alterations on the antioxidant enzyme activity and oxidative stress markers were partially restored by ketamine plus guanosine treatment. Taken together, these findings suggest that guanosine might potentiate the effects of ketamine on inflammatory and oxidative markers that are elevated in depression.

Cholecalciferol abolishes depressive-like behavior and hippocampal glucocorticoid receptor impairment induced by chronic corticosterone administration in mice.

Several attempts have been made to understand the role of cholecalciferol (vitamin D3) in the modulation of neuropsychiatric disorders. Notably, the deficiency of vitamin D3 is considered a pandemic and has been postulated to enhance the risk of major depressive disorder (MDD). Therefore, this study aims to investigate the antidepressant-like effect of cholecalciferol in a mouse model of depression induced by corticosterone, and the possible role of glucocorticoid receptors (GR), NLRP3 and autophagic pathways in this effect. Corticosterone administration (20 mg/kg, p.o., for 21 days) significantly increased the immobility time and grooming latency, as well as reduced the total time spent grooming in mice subjected to the tail suspension test (TST) and splash test (ST), respectively. Importantly, these behavioral alterations were associated with reduced GR immunocontent in the hippocampus of mice. Conversely, the repeated administration of cholecalciferol (2.5 µg/kg, p.o.) in the last 7 days of corticosterone administration was effective to prevent the increased immobility time in the TST and the reduced time spent grooming in the ST, and partially abolished the increase in the grooming latency induced by corticosterone, suggesting its antidepressant-like effect. These behavioral effects were similar to those exerted by fluoxetine (10 mg/kg, p.o.). Moreover, the corticosterone-induced reduction on hippocampal GR immunocontent was not observed in mice treated with cholecalciferol. Additionally, cholecalciferol treatment per se reduced the immunocontent of NLRP3 inflammasome-related proteins ASC, caspase-1, and TXNIP in the hippocampus of mice. No alterations on hippocampal immunocontent of the autophagic-related proteins phospho-mTORC1, beclin-1, and LC3A/B were observed following cholecalciferol treatment and/or corticosterone administration. Collectively, our results provide insights into the effects of cholecalciferol in depression-related behaviors that seem to be related, at least in part, to GR modulation.

Temperament traits moderate the relationship between Childhood Trauma and Interleukin 1ß profile in young adults.

Early life stressors, such as childhood trauma, have been associated to alterations in immune response that can last until adulthood. In this context, interleukin 1ß (IL-1ß) emerges as a pro-inflammatory cytokine with a pivotal role. Also, considering the temperament differences in stress susceptibility, and even immune dysfunction, studies investigating the complex interaction between these factors are scarce. Thus, the aim of the present study was to evaluate the moderating role of temperament traits in the relationship between childhood trauma and serum IL-1ß levels. This cross-sectional study consisted of 325 individuals, men and women, aged 18-35, enrolled from a population-based study in the city of Pelotas, Southern Brazil. Our main results indicate that higher serum levels of IL-1ß were associated with trauma severity (p < 0.01), and the variance of anger could explain 29% of IL-1ß increase in individuals who suffered severe trauma (p < 0.05). The effect of anger was considerably stronger in men than in women (46% and 25%, respectively). Moreover, the variance of sensitivity also explained 15% of IL-1ß increase (p < 0.05) as well as the variance of volition explained 11% of IL-1ß decrease (p < 0.05) in individuals who suffered severe trauma in the general population. Our results indicate that emotional individual differences can moderate the impact of childhood trauma on low-grade inflammation in young adults.

CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness.

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.

Protective Effects of Ursolic Acid Against Cytotoxicity Induced by Corticosterone: Role of Protein Kinases.

Neuronal hippocampal death can be induced by exacerbated levels of cortisol, a condition usually observed in patients with Major depressive disorder (MDD). Previous in vitro and in vivo studies showed that ursolic acid (UA) elicits antidepressant and neuroprotective properties. However, the protective effects of UA against glucocorticoid-induced cytotoxicity have never been addressed. Using an in vitro model of hippocampal cellular death induced by elevated levels of corticosterone, we investigated if UA prevents corticosterone-induced cytotoxicity in HT22 mouse hippocampal derived cells. Concentrations lower than 25 µM UA did not alter cell viability. Co-incubation with UA for 48 h was able to protect HT22 cells from the reduction on cell viability and from the increase in apoptotic cells induced by corticosterone. Inhibition of protein kinase A (PKA), protein kinase C (PKC) and, Ca2+/calmodulin-dependent protein kinase II (CaMKII), but not phosphoinositide 3-kinase(PI3K), by using the pharmacological the inhibitors: H-89, chelerythrine, KN-62, and LY294002, respectively totally abolished the cytoprotective effects of UA. Finally, UA abrogated the reduction in phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not in phospho-c-Jun kinases induced by corticosterone. These results indicate that the protective effect of UA against the cytotoxicity induced by corticosterone in HT22 cells may involve PKA, PKC, CaMKII, and ERK1/2 activation. The cytoprotective potential of UA against corticosterone-induced cytotoxicity and its ability to modulate intracellular signaling pathways involved in cell proliferation and survival suggest that UA may be a relevant strategy to manage stress-related disorders such as MDD.

Potential Role of Vitamin D for the Management of Depression and Anxiety.

Vitamin D, a fat-soluble vitamin, plays a role not only in calcium and phosphate homeostasis but also in several other functions, including cell growth and neuromuscular and immune function. The deficiency of vitamin D is highly prevalent throughout the world and has been suggested to be associated with an enhanced risk of major depressive disorder (MDD) and anxiety disorders. Therefore, vitamin D supplementation has been investigated for the prevention and treatment of these disorders. This review presents preclinical and clinical evidence of the effects of vitamin D supplementation in these disorders. Although preclinical studies provide limited evidence on the possible mechanisms underlying the beneficial effects of vitamin D for the management of these disorders, most of the clinical studies have indicated that vitamin D supplementation is associated with the reduction of symptoms of depression and anxiety, particularly when the supplementation was carried out in individuals with an MDD diagnosis (of the 13 studies in which MDD diagnosis was established, 12 had positive results with vitamin supplementation). However, some heterogeneity in the outcomes was observed and might be associated with an absence of overt psychiatric symptoms in several studies, genetic polymorphisms that alter vitamin D metabolism and bioavailability, differences in the supplementation regimen (monotherapy, adjunctive therapy, or large bolus dosing), and levels of 25-hydroxyvitamin D3 (25(OH)D) at baseline (individuals with low vitamin D status may respond better) and attained after supplementation. Additionally, factors such as sex, age, and symptom severity also need to be further explored in relation to the effects of vitamin D. Therefore, although vitamin D may hold significant potential for mental health, further preclinical and clinical studies are clearly necessary to better understand its role on mood/affect modulation.

Levels of 25-hydroxyvitamin D3, biochemical parameters and symptoms of depression and anxiety in healthy individuals.

Growing evidence support the role of vitamin D in brain function and behavior. This study investigated the relationship between 25-hydroxyvitamin D3 [25(OH)D3] levels, biochemical profile and symptoms of depression and anxiety in healthy individuals. Symptoms of depression were assessed by the Beck Depression Inventory (BDI) and anxiety was evaluated with the State-Trait Anxiety Inventory (STAI). Our sample included 36 individuals, mostly women 27(75%), 36.39 ± 9.72 years old, non-smokers 31(86.1%), body mass index of 26.57 ± 3.92 kg/m2, 27.95 ± 7.50% body fat. Participants were divided into those with 25(OH)D3 levels lower than 40 ng/mL (mean 28.16 ± 7.07) and equal or higher than 40 ng/mL (mean 53.19 ± 6.32). Those with lower 25(OH)D3 had higher levels of triacylglycerol, triacylglycerol/high density lipoprotein (HDL) ratio, high glucose and homeostatic model assessment of insulin resistance (HOMA-IR) index. No changes were observed in sociodemographic variables, body composition, inflammatory parameters and cortisol. Additionally, in the groups with low and high 25(OH)D3 levels, STAI state, STAI trait and BDI scores were not statistically different. Levels of 25(OH)D3 were inversely and independently associated with glucose and HOMA-IR, but not associated with triacylglycerol, depression and anxiety scores. Lower levels of 25(OH)D3 were associated with dysfunction in glucose metabolism but not with depression and anxiety in healthy individuals.