Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets.

The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation, mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. This review aims to highlight the inflammatory mechanisms (neuroinflammation, peripheral inflammation, and gut dysbiosis) involved in the pathophysiology of MDD and to explore novel anti-inflammatory therapeutic approaches for this psychiatric disturbance. Several lines of evidence have indicated that in addition to antidepressants, physical exercise, probiotics, and nutraceuticals (agmatine, ascorbic acid, and vitamin D) possess anti-inflammatory effects that may contribute to their antidepressant properties. Further studies are necessary to explore the therapeutic benefits of these alternative therapies for MDD.

Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise.

Major depressive disorder (MDD) has a high prevalence and is a major contributor to the global burden of disease. This psychiatric disorder results from a complex interaction between environmental and genetic factors. In recent years, the role of the gut microbiota in brain health has received particular attention, and compelling evidence has shown that patients suffering from depression have gut dysbiosis. Several studies have reported that gut dysbiosis-induced inflammation may cause and/or contribute to the development of depression through dysregulation of the gut-brain axis. Indeed, as a consequence of gut dysbiosis, neuroinflammatory alterations caused by microglial activation together with impairments in neuroplasticity may contribute to the development of depressive symptoms. The modulation of the gut microbiota has been recognized as a potential therapeutic strategy for the management of MMD. In this regard, physical exercise has been shown to positively change microbiota composition and diversity, and this can underlie, at least in part, its antidepressant effects. Given this, the present review will explore the relationship between physical exercise, gut microbiota and depression, with an emphasis on the potential of physical exercise as a non-invasive strategy for modulating the gut microbiota and, through this, regulating the gut-brain axis and alleviating MDD-related symptoms.

Visceral fat area measured by electrical bioimpedance as an aggravating factor of COVID-19: a study on body composition.

INTRODUCTION: Severe forms of COVID-19 are more common in patients with abnormal fat distribution, particularly high visceral adiposity. The patient's muscle strength may be reduced during the acute phase of the infection. Electrical bioimpedance (BIA) is a non-invasive method for measuring body compartments and estimating visceral fat area (VFA) that can be used at the bedside. OBJECTIVE: To assess the association between several body composition parameters, primarily high adipose tissue and high VFA, in patients with and without a diagnosis of COVID-19 infection, and whether it worsened the severity parameters. METHODS: This retrospective cohort study was conducted in a private hospital in the city of São Paulo from March 2020 to August 2021. The demographic and clinical data was collected from medical reports. Body composition is assessed using the InBODY® model S10 bioelectrical impedance device and a Jamar® digital hydraulic manual dynamometer with a scale from 0 to 90 kg is used to measure handgrip strength (HGS). RESULTS: A total of 96 patients with a mean age of 69.1 years (SD 15) were divided into two groups of 48 individuals, with and without COVID-19 infection. Body mass index (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.69, 11.83), fat mass (OR: 2.03, 95% CI: 0.48, 8.55), and VFA (OR: 1.08, 95% CI: 0.33, 3.53) were all higher in the infection group. When COVID-19 patients were evaluated, those with higher VFA had longer hospital stays (OR: 0.99, 95% CI: 0.97, 1.01) and used more vasoactive drugs (p = 0.043). Patients with COVID-19 with poor handgrip strength were 3.29 times more likely to require a prolonged intensive care unit (ICU) stay. CONCLUSION: The study concluded that excess weight and body fat are significantly associated with COVID-19 involvement, but the severity is primarily related to a greater area of visceral fat. The use of bioimpedance for visceral fat measurement was effective, as it is a simple method performed in the hospital setting that does not require the use of radiation.

Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking.

Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has received particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets have also been proposed. This study aimed to explore the possible multiple targets of ketamine enantiomers related to their antidepressant and antisuicidal effects. To this end, targets were predicted using Swiss Target Prediction software for each ketamine enantiomer. Targets related to depression and suicide were collected by the Gene Cards database. The intersections of targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Network pharmacology analysis was performed using Gene Mania and Cytoscape software. Molecular docking was used to predict the main targets of the network. The results indicated that esketamine and arketamine share some biological targets, particularly NMDA receptor and phosphodiesterases 3A, 7A, and 5A but have specific molecular targets. While esketamine is predicted to interact with the GABAergic system, arketamine may interact with macrophage migration inhibitory factor (MIF). Both ketamine enantiomers activate neuroplasticity-related signaling pathways and show addiction potential. Our results identified novel, poorly explored molecular targets that may be related to the beneficial effects of esketamine and arketamine against depression and suicide.

Neuroinflammation in Alzheimer's disease: potential beneficial effects of vitamin D.

Alzheimer's disease (AD) is the most common cause of dementia. In recent years, several studies have robustly shown that neuroinflammation plays a crucial role in the pathophysiology of this disease. The co-localization of amyloid-ß plaques near activated glial cells and the increased levels of inflammatory cytokines in AD patients indicate the involvement of the neuroinflammatory process in AD progression. Considering that pharmacological treatment remains a challenge for the management of this disease, compounds with anti-inflammatory and antioxidant properties are promising therapeutic strategies. In this context, vitamin D has gained attention in the last few years due to its neuroprotective property and the high prevalence of vitamin D deficiency in the population. Herein, in this narrative review we present the possible contribution of the antioxidant and anti-inflammatory properties of vitamin D for its neuroprotective effects, and the clinical and preclinical data dealing with the effects of vitamin D in AD, focusing mainly on the neuroinflammatory process.

NMDA receptor-mediated modulation on glutamine synthetase and glial glutamate transporter GLT-1 is involved in the antidepressant-like and neuroprotective effects of guanosine.

Guanosine has been reported to elicit antidepressant-like responses in rodents, but if these actions are associated with its ability to afford neuroprotection against glutamate-induced toxicity still needs to be fully understood. Therefore, this study investigated the antidepressant-like and neuroprotective effects elicited by guanosine in mice and evaluated the possible involvement of NMDA receptors, glutamine synthetase, and GLT-1 in these responses. We found that guanosine (0.05 mg/kg, but not 0.01 mg/kg, p. o.) was effective in producing an antidepressant-like effect and protecting hippocampal and prefrontocortical slices against glutamate-induced damage. Our results also unveiled that ketamine (1 mg/kg, but not 0.1 mg/kg, i. p, an NMDA receptor antagonist) effectively elicited antidepressant-like actions and protected hippocampal and prefrontocortical slices against glutamatergic toxicity. Furthermore, the combined administration of sub-effective doses of guanosine (0.01 mg/kg, p. o.) with ketamine (0.1 mg/kg, i. p.) promoted an antidepressant-like effect and augmented glutamine synthetase activity and GLT-1 immunocontent in the hippocampus, but not in the prefrontal cortex. Our results also showed that the combination of sub-effective doses of ketamine and guanosine, at the same protocol schedule that exhibited an antidepressant-like effect, effectively abolished glutamate-induced damage in hippocampal and prefrontocortical slices. Our in vitro results reinforce that guanosine, ketamine, or sub-effective concentrations of guanosine plus ketamine protect against glutamate exposure by modulating glutamine synthetase activity and GLT-1 levels. Finally, molecular docking analysis suggests that guanosine might interact with NMDA receptors at the ketamine or glycine/d-serine co-agonist binding sites. These findings provide support for the premise that guanosine has antidepressant-like effects and should be further investigated for depression management.

Patient experience and satisfaction with different temporomandibular joint treatments: A retrospective study.

This retrospective study aimed to evaluate patient satisfaction with different temporomandibular joint (TMJ) treatments. Patients were included in the study according to the following inclusion criteria: 1) arthrogenous and/or myogenous temporomandibular disorders (TMD); 2) Dimitroulis classification category between 1-4; 3) conservative treatment without any improvement at least for 3 months; 4) indication for one of the following TMD treatments: injection of botulinum toxin; arthrocentesis; arthroscopy, and open surgery without alloplastic material; and 5) age ≥16 years. An independent satisfaction questionnaire with 11 queries was applied via phone call to all patients, which included 6 questions using a 10-point Likert scale and 5 yes-or-no questions. The principal outcome was the overall satisfaction with the clinical result of the treatment, and the secondary outcomes were specific satisfaction with the following: 1) pain reduction; 2) range of mouth opening; 3) chewing ability; 4) postoperative recovery; 5) the fulfillment of expectations; 6) treatment choice; 7) treatment recommendation to a friend; and 8) the need for another intervention. Anxiety and depression were also included as variables. Data were analyzed using descriptive statistics, non-parametric Kruskal-Wallis and Spearman rank correlation coefficient tests. A total of 120 patients (mean age 41.20 ± 17.78 years) were enrolled, comprising 109 women (90%) and 11 men (10%). The overall clinical satisfaction of all patients was 8.24 ± 2.23 (mean ± SD), and 97 patients (80.8%) stated that they would repeat the treatment. Patients submitted to TMJ arthrocentesis and arthroscopy had higher overall clinical satisfaction (9.09 ± 0.971 and 9.03 ± 1.13, p = 0.021) followed by open surgery (8.38 ± 1.84). The authors observed three statistically significant correlations: 1) overall clinical satisfaction and patient expectations (r = 0.803; p < 0.0001); 2) overall clinical satisfaction and post-treatment pain (r = -0.299; p = 0.003); and (3) the presence of depression and the need for further TMJ treatment (r = 0.186; p = 0.043). Within the limitations of the study it seems that patient expectations should be addressed ad initium, and the presence of a diagnosis of depression with concomitant TMD must alert the clinical team and patient for the possible need of additional treatment.

Suicide rates in Ecuador: A nationwide study from 2011 until 2020.

Suicide, suicide ideations, and psychiatric disorder rates tend to increase after natural disasters such as earthquake. In 2016 Ecuador experienced a 7.8Mw earthquake and, more recently, the Covid-19 confinement. Both events may have negatively affected the mental health of the Ecuadorian population. Therefore, the present study aimed to evaluate the suicide rates and choice of suicide method in the Ecuadorian population between January 2011 and December 2020. The dataset used is publicly available on the Ecuadorian National Institute of Statistics and Censuses. Multivariate logistic regression models were used to calculate adjusted odds ratios (OR) for potential sociodemographic factors associated with each suicide method compared to other reported suicide methods. There were 10,380 registered cases of suicide in Ecuador between 2011 and 2020. Significant suicide rates per provinces were seen in Napo with 12.63 and Azuay with 12.52, followed by Bolívar with 12.30, and Orellana with 11.36 suicides/100,000 habitants. Hanging accounted for 7082 cases (68.2 %). The mestizos (82 %) were the most prevalent ethnicity of all suicide cases. School-age children with 6-12 years (OR 8.83, 95 % CI 5.34-14.59) and adolescents with 13-19 years (OR 1.46, 95 % CI 1.29-1.66) were more likely to use hanging as method of suicide. In conclusion, we observed an increase of suicide rates from 8.15 per 100,000 in 2011 to 8.81 in 2020. The confinement of COVID-19 pandemic in the period evaluated did not significantly affect the suicide rates. An increased suicide rate was observed in the province hardest hit by the 2016 earthquake.

The antidepressant-like effect of guanosine involves the modulation of adenosine A1 and A2A receptors.

Guanosine has been considered a promising candidate for antidepressant responses, but if this nucleoside could modulate adenosine A1 (A1R) and A2A (A2AR) receptors to exert antidepressant-like actions remains to be elucidated. This study investigated the role of A1R and A2AR in the antidepressant-like response of guanosine in the mouse tail suspension test and molecular interactions between guanosine and A1R and A2AR by docking analysis. The acute (60 min) administration of guanosine (0.05 mg/kg, p.o.) significantly decreased the immobility time in the tail suspension test, without affecting the locomotor performance in the open-field test, suggesting an antidepressant-like effect. This behavioral response was paralleled with increased A1R and reduced A2AR immunocontent in the hippocampus, but not in the prefrontal cortex, of mice. Guanosine-mediated antidepressant-like effect was not altered by the pretreatment with caffeine (3 mg/kg, i.p., a non-selective adenosine A1R/A2AR antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX - 2 mg/kg, i.p., a selective adenosine A1R antagonist), or 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385 - 1 mg/kg, i.p., a selective adenosine A2AR antagonist). However, the antidepressant-like response of guanosine was completely abolished by adenosine (0.5 mg/kg, i.p., a non-selective adenosine A1R/A2AR agonist), N-6-cyclohexyladenosine (CHA - 0.05 mg/kg, i.p., a selective adenosine A1 receptor agonist), and N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA - 0.1 mg/kg, i.p., a selective adenosine A2A receptor agonist). Finally, docking analysis also indicated that guanosine might interact with A1R and A2AR at the adenosine binding site. Overall, this study reinforces the antidepressant-like of guanosine and unveils a previously unexplored modulation of the modulation of A1R and A2AR in its antidepressant-like effect.

The antidepressant-like effect elicited by vitamin D3 is associated with BDNF/TrkB-related synaptic protein synthesis.

Vitamin D3 (cholecalciferol) has been shown to exert antidepressant-like responses, but the role BDNF/TrkB-related synaptic plasticity in this effect remains to be established. Thus, this study investigated the time-course antidepressant-like response of vitamin D3 in female and male mice and the possible role of BDNF/TrkB signaling in this response. The repeated (7 and 21 days), but not acute (60 min), administration of vitamin D3 (2.5 µg/kg, p.o.) exerted an antidepressant-like effect in female and male mice subjected to the tail suspension test, without altering the basal locomotor activity in the open-field test. Notably, vitamin D3 caused a similar time-dependent antidepressant-like effect in male and female mice, suggesting that this behavioral response in the tail suspension test might not be affected by sex differences. Vitamin D3 administration for 21 days, but not for 7 days or 1 h, augmented BDNF levels in the hippocampus and prefrontal cortex of mice. No effects on phospho-CREB/CREB levels were detected in the hippocampus and prefrontal cortex after chronic vitamin D3 administration. Additionally, vitamin D3 increased TrkB, GluA1, and PSD-95 levels in the prefrontal cortex, but not in the hippocampus. Furthermore, an upregulation of synapsin level was observed in both brain regions after vitamin D3 administration. These findings reinforce and extend the notion that vitamin D3 is effective to produce antidepressant-like responses in male and female mice and provide novel evidence that this effect could be associated with BDNF/TrkB-related synaptic protein synthesis. Finally, vitamin D3 could be a feasible nutritional strategy for the management of depression.

Impact of the Nutritional Status on Clinical Outcomes of Patients with Coronavirus Disease Undergoing Cancer Treatment.

Coronavirus disease (COVID-19) is a critical and potentially fatal condition. The nutritional status affects the evolution and clinical outcome throughout the disease course among factors influencing the patient prognosis. In patients with cancer, the Patient-Generated Subjective Global Assessment (PG-SGA) is the preferred instrument for assessing the nutritional status. The aim of this retrospective cross-sectional study was to evaluate the impact of the nutritional status on the clinical outcome of patients with COVID-19 undergoing cancer treatment. We enrolled 52 patients with cancer under outpatient follow-up who had been diagnosed with COVID-19 during the cancer treatment course. The PG-SGA instrument revealed age (p = 0.045) and nutritional status (p = 0.042) before infection as the main risk factors of death from COVID-19. In addition, the risk of mortality due to COVID-19 increased with the degree of malnutrition. Twelve (23.1%) of the 52 patients showed no negative effects related to COVID-19, and age below 65 years was considered to be a protective factor.

SARS-CoV-2 consequences for mental health: Neuroinflammatory pathways linking COVID-19 to anxiety and depression.

The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increased prevalence of mental health disorders, particularly anxiety and depression. Moreover, the COVID-19 pandemic has caused stress in people worldwide due to several factors, including fear of infection; social isolation; difficulty in adapting to new routines; lack of coping methods; high exposure to social media, misinformation, and fake reports; economic impact of the measures implemented to slow the contagion and concerns regarding the disease pathogenesis. COVID-19 patients have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, and other inflammation-related factors. Furthermore, invasion of the central nervous system by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may potentially contribute to neuroinflammatory alterations in infected individuals. Neuroinflammation, a consequence of psychological stress due to the COVID-19 pandemic, may also play a role in the development of anxiety and depressive symptoms in the general population. Considering that neuroinflammation plays a significant role in the pathophysiology of depression and anxiety, this study investigated the effects of SARS-CoV-2 on mental health and focused on the impact of the COVID-19 pandemic on the neuroinflammatory pathways.

Molecular Basis Underlying the Therapeutic Potential of Vitamin D for the Treatment of Depression and Anxiety.

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium-phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.

Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.

Guanosine as a promising target for fast-acting antidepressant responses.

Although the rapid-onset and sustained antidepressant responses elicited by ketamine have gained considerable attention in recent years, it has some knock-on effects that limit its widespread clinical use. Therefore, ketamine is considered the prototype for the new generation of glutamate-based rapid-acting antidepressants. Within this context, it has been demonstrated that guanosine, an endogenous guanine-based purine, has overlapping mechanisms of action with ketamine and is effective in eliciting fast antidepressant-like responses and even potentiating ketamine's actions in preclinical studies. Here, we review the recent findings regarding the ability of guanosine to produce rapid-acting antidepressant-like effects and we provide an overview of the molecular mechanisms underlying its antidepressant-like actions. Moreover, the neurobiological mechanisms underpinning the ability of guanosine in boosting the antidepressant-like and pro-synaptogenic effects elicited by ketamine are also reported. Taken together, this review opens perspectives for the use of guanosine alone or in combination with ketamine for the management of treatment-resistant depression.

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25 µg/kg, p.o.) for 7 days, similar to fluoxetine (10 mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100 mg/kg, i.p., for 4 days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21 days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7 days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.

Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway.

The mTORC1-dependent dendritic spines formation represents a key mechanism for fast and long-lasting antidepressant responses, but it remains to be determined whether this mechanism may account for the ability of guanosine in potentiating ketamine's actions. Here, we investigated the ability of ketamine plus guanosine to elicit fast and sustained antidepressant-like and pro-synaptogenic effects in mice and the role of mTORC1 signaling in these responses. The combined administration of subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) caused a fast (1 h - 24 h), but not long-lasting (7 days) reduction in the immobility time in the tail suspension test. This behavioral effect was paralleled by a rapid (started in 1 h) and transient (back to baseline in 24 h) increase on BDNF, p-Akt (Ser473), p-GSK-3ß (Ser9), p-mTORC1 (Ser2448), p-p70S6K (Thr389) immunocontent in the hippocampus, but not in the prefrontal cortex. Conversely, ketamine plus guanosine increased PSD-95 and GluA1 immunocontent in the prefrontal cortex, but not the hippocampus after 1 h, whereas increased levels of these proteins in both brain structures were observed after 24 h, but these effects did not persist after 7 days. The combined administration of ketamine plus guanosine raised the dendritic spines density in the ventral hippocampal DG and prefrontal cortex after 24 h Rapamycin (0.2 nmol/site, i.c.v.) abrogated the antidepressant-like effect and pro-synaptogenic responses triggered by ketamine plus guanosine. These results indicate that guanosine may boost the antidepressant-like effect of ketamine for up to 24 h by a mTORC1-dependent mechanism.

Prophylactic efficacy of ketamine, but not the low-trapping NMDA receptor antagonist AZD6765, against stress-induced maladaptive behavior and 4E-BP1-related synaptic protein synthesis impairment.

Ketamine enhances the resilience against stress-induced depressive-like behavior, but its prophylactic efficacy in anxiety-related behaviors remains to be elucidated. Moreover, there is a need for developing novel preventive strategies against depressive- and anxiety-like behavior. AZD6765, a low-trapping NMDA receptor antagonist, shares with ketamine common molecular targets and produces rapid-onset antidepressant effects, suggesting that it could be a prophylactic agent. Therefore, this study investigated the prophylactic effect of ketamine against the depressive- and anxiety-like behavior induced by chronic restraint stress (2 h/day, for 10 days) in mice. We also investigated if AZD6765 exerts a resilience-enhancing response against these maladaptive behaviors. The contribution of 4E-BP1-related synaptic proteins synthesis (PSD-95/GluA1) in the possible pro-resilience efficacy of ketamine and AZD6765 was investigated. A single administration of ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), given 1 week before the stress protocol, was effective in preventing stress-induced depressive-like behavior in the tail suspension test and splash test. Ketamine administered at 1 and 5 mg/kg (i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), prevented stress-induced anxiety-related self-grooming alterations. Stress-induced reduction on 4E-BP1 phosphorylation and PSD-95 and GluA1 immunocontent in the prefrontal cortex was prevented by ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.). The results indicate that ketamine, but not AZD6765, exerts a pro-resilience response against stress-induced maladaptive behavior, reinforcing that it could be a prophylactic agent to manage individuals at-risk to develop MDD and anxiety.

NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD.

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.