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.

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.

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 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.

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.

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.

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.

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.

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.

Vitamin E for the management of major depressive disorder: possible role of the anti-inflammatory and antioxidant systems.

OBJECTIVES: Vitamin E has various functions in humans, including antioxidant, anti-inflammatory, anti-cancer, and anti-atherogenic actions, as well as direct effects on enzymatic activities and modulation of gene transcription. In addition to these functions, vitamin E is also important for the central nervous system, and its role in the prevention and/or treatment of some neurological diseases has been suggested. In particular, the role of vitamin E in the modulation of major depressive disorder (MDD) is an issue that has emerged in recent studies. Many factors have been implicated in the pathophysiology of this disorder, including inflammation, oxidative, and nitrosative stress. METHODS: This narrative review discusses the involvement of inflammation, oxidative, and nitrosative stress in the pathophysiology of MDD and presents clinical and preclinical studies that correlate vitamin E with this psychiatric disorder. RESULTS: We gathered evidence from clinical studies that demonstrated the relationship between low vitamin E status and MDD symptoms. Vitamin E has been reported to exert a beneficial influence on the oxidative and inflammatory status of individuals, factors that may account for the attenuation of depressive symptoms. Preclinical studies have reinforced the antidepressant-like response of vitamin E, and the mechanisms underlying its effect seem to be related to the modulation of oxidative stress and neuroinflammation. CONCLUSION: We suggest that vitamin E has potential to be used as an adjuvant for the management of MDD, but more studies are clearly needed to ascertain the efficacy of vitamin E for alleviating depressive symptoms.

Functional role of ascorbic acid in the central nervous system: a focus on neurogenic and synaptogenic processes.

Ascorbic acid, a water-soluble vitamin, is highly concentrated in the brain and participates in neuronal modulation and regulation of central nervous system (CNS) homeostasis. Ascorbic acid has emerged as a neuroprotective compound against neurotoxicants and neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Moreover, it improves behavioral and biochemical alterations in psychiatric disorders, including schizophrenia, anxiety, major depressive disorder, and bipolar disorder. Some recent studies have advanced the knowledge on the mechanisms associated with the preventive and therapeutic effects of ascorbic acid by showing that they are linked to improved neurogenesis and synaptic plasticity. This review shows that ascorbic acid has the potential to regulate positively stem cell generation and proliferation. Moreover, it improves neuronal differentiation of precursors cells, promotes adult hippocampal neurogenesis, and has synaptogenic effects that are possibly linked to its protective or therapeutic effects in the brain.

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.

Agmatine as a novel candidate for rapid-onset antidepressant response.

Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

The resilient phenotype elicited by ketamine against inflammatory stressors-induced depressive-like behavior is associated with NLRP3-driven signaling pathway.

Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS - 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-α - 0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-α administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-α, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1ß in this brain region, while TNF-α only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-α administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway.