Pre- and Post-Synaptic protein in the major depressive Disorder: From neurobiology to therapeutic targets.

Major depressive disorder (MDD) has demonstrated its negative impact on various aspects of the lives of those affected. Although several therapies have been developed over the years, it remains a challenge for mental health professionals. Thus, understanding the pathophysiology of MDD is necessary to improve existing treatment options or seek new therapeutic alternatives. Clinical and preclinical studies in animal models of depression have shown the involvement of synaptic plasticity in both the development of MDD and the response to available drugs. However, synaptic plasticity involves a cascade of events, including the action of presynaptic proteins such as synaptophysin and synapsins and postsynaptic proteins such as postsynaptic density-95 (PSD-95). Additionally, several factors can negatively impact the process of spinogenesis/neurogenesis, which are related to many outcomes, including MDD. Thus, this narrative review aims to deepen the understanding of the involvement of synaptic formations and their components in the pathophysiology and treatment of MDD.

Major depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities.

Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation.

Circadian Rhythms and Sleep Disorders Associated to Major Depressive Disorder: Pathophysiology and Therapeutic Opportunities.

Major depressive disorder (MDD) is a complex mood disorder. While much progress has been made in understanding the pathophysiology of MDD, no single mechanism can explain all facets of this disorder. Several studies show that disturbances in biological rhythms can lead to the development of MDD. Indeed, insomnia or hypersomnia are symptoms included in the MDD diagnostic criteria. Clinical studies and meta-analyses showed a strong relationship between MDD and sleep disorders. Sleep disorder and MDD are associated with activation in the hypothalamicpituitary-adrenal (HPA) axis and inflammation. The increase in inflammatory response can activate the kynurenine pathway, decrease serotonin synthesis, and affect other factors involved in the pathophysiology of neuropsychiatric conditions. Moreover, sleep disorders and MDD can change the gut microbiota and alter the microbiota-gut-brain axis. Thus, this review discusses the relationship between MDD, circadian rhythms, and sleep disorders, describing the potential pathophysiological mechanism shared in these conditions. In addition, therapeutic opportunities based on antiinflammatory, antioxidant, HPA axis regulatory, and synapse-modulating actions are raised. For the article search, we used the PubMed database. Both sleep disorders and changes in biological rhythms have a bidirectional relationship with MDD. Although some pathophysiological mechanisms, including inflammation, changes in the gut microbiota, and decreased neuroplasticity, may be involved in the relationship between sleep, circadian rhythms, and MDD, other mechanisms are not yet well understood. Therapeutic opportunities based on anti-inflammatory, antioxidant, HPA regulatory axis, and synapse modulating actions appear to be promising targets in preventing MDD, circadian rhythm disturbances, and sleep disorders.

Natural Phytochemicals for the Treatment of Major Depressive Disorder: A Mini-Review of Pre- and Clinical Studies.

Major Depressive Disorder (MDD) is a common mental illness that causes significant disability and declining quality of life. An overlap of multiple factors can be involved in the pathophysiology of this mood disorder, including increased inflammation and oxidative stress, change in neurotransmitters, decreased brain-derived neurotrophic factor (BDNF), activation of the hypothalamicpituitary- adrenal (HPA) axis, and changes in the microbiota-gut-brain axis. Although the classic treatment for MDD is safe, it is far from ideal, with delay to start the best clinic, side effects, and a large number of non-responses or partial-responses. Therefore, other alternatives are being studied to improve depressive symptoms, and, among them, the role of phytochemicals in food stands out. This mini-review will discuss the main phytochemicals present in foods with clinical and preclinical studies showing benefits for MDD treatment. In addition, the main mechanisms of action that are being proposed for each of these compounds will be addressed.

Environmental Enrichment Rescues Oxidative Stress and Behavioral Impairments Induced by Maternal Care Deprivation: Sex- and Developmental-Dependent Differences.

Stress is related to major depressive disorder (MDD). This study investigated the action that early stress, represented by maternal deprivation (MD), has on the behavior and oxidative stress of Wistar female and male rats. Also, it was evaluated whether changes induced by MD could be reversed by environmental enrichment (EE). Male and female rats were divided into a non-MD and MD group. The MD group was subdivided into 3 groups: (1) assessed on the 31st day after exposure to EE for 10 days, (2) assessed on the 41st day after exposure to EE for 20 days, and (3) assessed on the 61st day after exposure to EE for 40 days. Behavioral tests were performed (memory habituation and elevated plus maze). Oxidative stress parameters were evaluated peripherally. MD was able to promote anxiety-like behavior at postnatal day (PND) 41 and impair memory at PND 31 and PND 61 in male and PND 41 and PND 61 in female rats. MD was associated with increased oxidative stress parameters (reactive species to thiobarbituric acid levels (TBARS), carbonylated proteins, nitrite/nitrate concentration), and altered antioxidant defenses (superoxide dismutase (SOD) and catalase (CAT), and sulfhydryl content) in different stages of development. The EE was able to reverse almost all behavioral and biochemical changes induced by MD; however, EE effects were sex and developmental period dependent. These findings reinforce the understanding of the gender variable as a biological factor in MDD related to MD and EE could be considered a treatment option for MDD treatment and its comorbidities.

Beneficial effects and neurobiological aspects of environmental enrichment associated to major depressive disorder and autism spectrum disorder.

A suitable enriched environment favors development but can also influence behavior and neuronal circuits throughout development. Studies have shown that environmental enrichment (EE) can be used as an essential tool or combined with conventional treatments to improve psychiatric and neurological symptoms, including major depressive disorder (MDD) and autism spectrum disorder (ASD). Both disorders affect a significant percentage of the wofrld's population and have complex pathophysiology. Moreover, the available treatments for MDD and ASD are still inadequate for many affected individuals. Experimental models demonstrate that EE has significant positive effects on behavioral modulation. In addition, EE has effects on neurobiology, including improvement in synaptic connections and neuroplasticity, modulation of neurotransmissions, a decrease in inflammation and oxidative stress, and other neurobiology effects that can be involved in the pathophysiology of MDD and ASD. Thus, this review aims to describe the leading behavioral and neurobiological effects associated with EE in MDD and ASD.

Sex differences on the response to antidepressants and psychobiotics following early life stress in rats.

Major depressive disorder (MDD) is the most prevalent mood disorder globally. Most antidepressants available for the treatment of MDD increase the concentration of monoamines in the synaptic cleft. However, such drugs have a high latency time to obtain benefits. Thus, new antidepressants with fast action and robust efficacy are very important. This study evaluated the effects of escitalopram, ketamine, and probiotic Bifidobacterium infantis in rats submitted to the maternal deprivation (MD). MD rats received saline, escitalopram, ketamine, or probiotic for 10, 30, or 50 days, depending on the postnatal day (PND):21, 41, and 61. Following behavior, this study examined the integrity of the blood-brain barrier (BBB) and oxidative stress markers. MD induced depressive-like behavior in females with PND21 and males with PND61. All treatments reversed depressive-like behavior in females and escitalopram and ketamine in males. MD induced an increase in the permeability of the BBB, an imbalance between oxidative stress and antioxidant defenses. Treatments regulated the oxidative damage and the integrity of the BBB induced by MD. The treatment with escitalopram, ketamine, or probiotics may prevent behavioral and neurochemical changes associated with MDD, depending on the developmental period and gender.

Relationship between sleep duration and quality and mental health before and during COVID-19 pandemic: Results of population-based studies in Brazil.

OBJECTIVE: This study aimed to evaluate the association between sleep duration and quality and mental health before and amid the COVID-19 pandemic. METHODS: Data from two population-based cross-sectional studies conducted in 2019 and 2020 with adults in Criciúma, Southern Brazil. The Patient Health Questionnaire-9 (PHQ-9) was used to screen major depressive episodes, while the perceived stress scale was used to assess perceived stress. Sleep was evaluated through self-reported duration and quality. Crude and adjusted Poisson regression models were used to assess the association between sleep and mental health disorders. RESULTS: A total of 820 (in 2019) and 863 subjects (in 2020) were assessed. Sleep quality presented significant associations with depression and stress in both years, and the magnitude of the association with depression increased amid COVID-19 pandemic. In individuals with poor/very poor sleep quality, the risk of depression in 2019 was 2.14 (95%IC 1.48;3.09) higher when compared to those with good/very good sleep quality. This risk increased to 2.26 (95%IC 1.49;3.40) in 2020. The risk of stress was 1.90 (95%IC 1.42;2.55) in 2019 and 1.66 (95%IC1.34;2.07) in 2020. The sleep duration was not associated with mental health disorders in the adjusted analyses. CONCLUSION: The results provide important evidence that sleep quality can influence mental health of adults. The COVID-19 pandemic seems to have had a considerable impact on this association.

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.

Microbiota-Gut-Brain Communication in the SARS-CoV-2 Infection.

The coronavirus disease of 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). In addition to pneumonia, individuals affected by the disease have neurological symptoms. Indeed, SARS-CoV-2 has a neuroinvasive capacity. It is known that the infection caused by SARS-CoV-2 leads to a cytokine storm. An exacerbated inflammatory state can lead to the blood-brain barrier (BBB) damage as well as to intestinal dysbiosis. These changes, in turn, are associated with microglial activation and reactivity of astrocytes that can promote the degeneration of neurons and be associated with the development of psychiatric disorders and neurodegenerative diseases. Studies also have been shown that SARS-CoV-2 alters the composition and functional activity of the gut microbiota. The microbiota-gut-brain axis provides a bidirectional homeostatic communication pathway. Thus, this review focuses on studies that show the relationship between inflammation and the gut microbiota-brain axis in SARS-CoV-2 infection.

In Pursuit of Healthy Aging: Effects of Nutrition on Brain Function.

Consuming a balanced, nutritious diet is important for maintaining health, especially as individuals age. Several studies suggest that consuming a diet rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and fish may reduce age-related cognitive decline and the risk of developing various neurodegenerative diseases. Numerous studies have been published over the last decade focusing on nutrition and how this impacts health. The main objective of the current article is to review the data linking the role of diet and nutrition with aging and age-related cognitive decline. Specifically, we discuss the roles of micronutrients and macronutrients and provide an overview of how the gut microbiota-gut-brain axis and nutrition impact brain function in general and cognitive processes in particular during aging. We propose that dietary interventions designed to optimize the levels of macro and micronutrients and maximize the functioning of the microbiota-gut-brain axis can be of therapeutic value for improving cognitive functioning, particularly during aging.

Environmental enrichment improves lifelong persistent behavioral and epigenetic changes induced by early-life stress.

This study aimed to evaluate the effects of environmental enrichment (EE) in Wistar rats subjected to maternal deprivation (MD). MD was performed in the first post-natal days (PND) ten for 3 h/day. The groups were: control; deprived without EE; and deprived with EE. The EE was applied for 3 h/day. Forced swimming test (FST) and open field test were performed, and histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities in the prefrontal cortex (PFC) and hippocampus were evaluated on 31, 41, and 61 PND. MD altered spontaneous locomotor activity and immobility time in FST, but the effects were sex- and developmental period dependent. In deprived females at PND 31, 41, and 61, HDAC and DNMT increased in the PFC and hippocampus. In females exposed to EE for 20 days, there was a decrease of HDAC in the hippocampus and DNMT in the PFC and hippocampus. Exposure of females to EE for 40 days can reverse HDAC and DNMT increase in all brain areas. In deprived males at PND 31, 41, and 61, HDAC and DNMT increased in the hippocampus, and in the group exposed to EE for 40 days, there was a decrease in hippocampal activity. In PFC of male deprived rats at PND 61 and EE for 40 days, there was a reduction of HDAC and DNMT. MD induced lifelong persistent behavioral and epigenetic changes, and such effects were more evident in female than male rats. EE can be considered an essential non-pharmacological strategy to treat long-term trauma-induced early life changes.

Sex-related patterns of the gut-microbiota-brain axis in the neuropsychiatric conditions.

Sex differences are often observed in psychiatric patients, especially major depressive disorders (MDD), schizophrenia, and developmental disorders, including autism spectrum disorders (ASDs). The prevalence rates between males and females seem variate according to the clinical condition. Although the findings are still incipient, it is suggested that these differences can involve neuroanatomical, neurochemical, and physiological sex differences. In this context, the microbiota-gut-brain axis hypothesis arises to explain some aspects of the complex pathophysiology of neuropsychiatric disorders. The microbiota composition is host-specific and can change conforming to age, sex, diet, medication, exercise, and others. The communication between the brain and the gut is bidirectional and may impact the entire system homeostasis. Many pathways appear to be involved, including neuroanatomic communication, neuroendocrine pathways, immune system, bacteria-derived metabolites, hormones, neurotransmitters, and neurotrophic factors. Although the clinical and preclinical studies are sparse and not very consistent, they suggest that sex differences in the gut microbiota may play an essential role in some neuropsychiatric conditions. Thus, this narrative review has as a mainly aim to show the points sex-related patterns associated to the gut-microbiota-brain axis in the MDD, ASDs, and schizophrenia.

The influence of diet quality on depression among adults and elderly: A population-based study.

BACKGROUND: Depression is the most common mental illness, achieving more than 264 million people worldwide. Although diet quality may be associated with depression symptoms, this relationship has not been deeply investigated among Brazilians. Therefore, this study was conducted to evaluate this relationship. METHODS: This is a population-based cross-sectional study with representative individuals aged 18 years or over living in an urban area. Individuals were selected using a multistage sampling procedure. The Patient Health Questionnaire-9 was used to screen for major depressive episodes, and a Food Frequency Questionnaire was used to evaluate diet. We used a hierarchical model to conduct the analyses and calculated prevalence ratio using Poisson regression. RESULTS: A total of 820 subjects were assessed, with mean age of 54.8 (±17.4) years. Prevalence of major depressive episodes was 29.2%. After final adjustment, diet quality remained directly associated with depression (p = 0.024). Individuals with the worst diet quality were 39% more likely to have major depressive episodes when compared to those who had the best diet quality. Depression was also associated with consumption of soda or artificial juice and are food markers of unhealthy diets. LIMITATIONS: The cross-sectional design does not establish whether the associations are causal, and the Patient Health Questionnaire-9 is a screening scale - not a diagnostic tool; however, it is easy, quick to apply, and is widely used in epidemiological studies. CONCLUSION: The results provide important evidence about the role of diets on that mood disorder, which contributes to management approaches to depression.

Antidepressant effects of creatine on amyloid ß1-40-treated mice: The role of GSK-3ß/Nrf2 pathway.

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neuronal lost in specific brain areas including hippocampus, resulting in memory/learning deficits and cognitive impairments. In addition, non-cognitive symptoms are reported in AD patients, such as anxiety, apathy and depressed mood. The current antidepressant drugs present reduced efficacy to improve depressive symptoms in AD patients. Here, we investigated the ability of creatine, a compound with neuroprotective and antidepressant properties, to counteract amyloid ß1-40 peptide-induced depressive-like behavior in mice. Moreover, we addressed the participation of the intracellular signaling pathway mediated by glycogen synthase kinase-3ß (GSK-3ß)/nuclear factor erythroid-2-related factor 2 (Nrf2) in the creatine effects. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased the immobility time in the tail suspension test and decreased the grooming time and increased latency to grooming in the splash test, indicative of depressive-like behavior. These impairments were attenuated by creatine (0.01 and 10 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o., positive control). No significant alterations on locomotor performance were observed in the open field. Aß1-40 administration did not alter hippocampal phospho-GSK-3ß (Ser9)/total GSK-3ß, total GSK-3ß and heme oxygenase-1 (HO-1) immunocontents. However, Aß1-40-infused mice treated with creatine (0.01 mg/kg) presented increased phosphorylation of GSK-3ß(Ser9) and HO-1 immunocontent in the hippocampus. Fluoxetine per se increased GSK-3ß(Ser9) phosphorylation, but did not alter HO-1 levels. In addition, Aß1-40 administration increased hippocampal glutathione (GSH) levels as well as glutathione reductase (GR) and thioredoxin reductase (TrxR) activities, and these effects were abolished by creatine and fluoxetine. This study provides the first evidence of the antidepressive-like effects of creatine in Aß1-40-treated mice, which were accompanied by hippocampal inhibition of GSK-3ß and modulation of antioxidant defenses. These findings indicate the potential of creatine for the treatment of depression associated with AD.

Depression and peripheral inflammatory profile of patients with obesity.

This narrative review will present and discuss clinical data from 16 cross-sectional and 6 longitudinal studies examining the relationship between body mass index (BMI), symptoms of depression and peripheral inflammation. Our aim is to determine which of obesity and depression contributes best to the peripheral low-grade inflammation frequently associated to both conditions. Studies including a complete evaluation of inflammatory markers are scarce and high levels of interleukin-6 (IL-6) and C-reactive protein (CRP) are the most consistent findings associated with obesity and symptoms of depression. Among the cross-sectional studies, seven studies, including a total of 9421 individuals, pointed to BMI as the major factor associated with systemic low-grade inflammation. However, in four studies, including 16,837 individuals, CRP levels remained associated with the symptoms of depression even after correction for BMI, suggestion that in the absence of overweight or obesity other sources of peripheral inflammation might contribute to presence of depressive symptoms. Additionally, another five studies, including 5569 individuals failed to find an association between depression and peripheral inflammation, reinforcing the heterogeneity of this condition. In the longitudinal data, changes in BMI were associated with a reduction in depressive scores at follow-up, after bariatric surgery or after diet. In four longitudinal studies, high levels of CRP were found to be associated with depression even after adjustment for BMI and weight loss, further corroborating the idea that other sources of peripheral inflammation might contribute to depressive symptoms. Thus it seems that both obesity and depressive symptoms can contribute to peripheral inflammation, and once installed the presence of inflammation can contribute to several behavioral alterations that reinforce the cyclic pattern of co-occurrence observed in patients with obesity and MDD. Future clinical studies should focus on strategic efforts to collect new data and to improve or standardize methods for the evaluation of depression, body composition and a more complete inflammatory profile. These approaches are essential for the development of pharmacological and/or non-pharmacological strategies designed to break this cyclic pattern of co-occurrence.

Evidence for the involvement of heme oxygenase-1 in the antidepressant-like effect of zinc.

BACKGROUND: Considering that heme oxygenase-1 (HO-1) and the brain-derived neurotrophic factor (BDNF)-mediated pathway are involved in the pathophysiology of depression and that zinc has been shown to exert beneficial effects in the management of depression, this study investigated the influence of these targets on the antidepressant-like effect of zinc. METHODS: Mice were treated with sub-effective or effective doses of zinc chloride (ZnCl2, 10mg/kg, po), and 45min later, they received intracerebroventricular (icv) injections of sub-effective doses of either zinc protoporphyrin IX (ZnPP, 10µg/mouse, HO-1 inhibitor), cobalt protoporphyrin IX (CoPP, 0.01µg/mouse, HO-1 inducer) or K-252a (1µg/mouse, TrkB receptor antagonist). Immobility time and locomotor activity were evaluated through the tail suspension test (TST) and open-field test (OFT), respectively. HO-1 immunocontents were evaluated in the prefrontal cortex and hippocampus 60min after ZnCl2 (10mg/kg, po) treatment. RESULTS: The antidepressant-like effect of ZnCl2 was prevented by the treatment with ZnPP and K-252a. Furthermore, sub-effective doses of CoPP and ZnCl2 produced a synergistic antidepressant-like effect in the TST. None of the treatments altered locomotor activity. ZnCl2 administration increased HO-1 immunocontents only in the prefrontal cortex. CONCLUSIONS: The results indicate that the antidepressant-like effect of ZnCl2 in the TST may depend on the induction of HO-1, and activation of TrkB receptor.

Involvement of glutamatergic neurotransmission in the antidepressant-like effect of zinc in the chronic unpredictable stress model of depression.

Stress and excessive glutamatergic neurotransmission have been implicated in the pathophysiology of depression. Therefore, this study was aimed at investigating the influence of zinc on depressive-like behavior induced by chronic unpredictable stress (CUS), on alterations in glutamate-induced toxicity and immunocontent of proteins involved in the control of glutamatergic neurotransmission in the hippocampus of mice. Mice were subjected to CUS procedure for 14 days. From the 8th to the 14th day, mice received zinc chloride (ZnCl2) (10 mg/kg) or fluoxetine (10 mg/kg, positive control) once a day by oral route. CUS caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test (TST), which was prevented by treatment with ZnCl2 or fluoxetine. Ex vivo exposure of hippocampal slices to glutamate (10 mM) resulted in a significant decrease on cell viability; however, neither CUS procedure nor drug treatments altered this reduction. No alterations in the immunocontents of GLT-1 and GFAP or p-Akt were observed in any experimental group. The ratio of p-Akt/AKT was also not altered in any group. However, Akt immunocontent was increased in stressed mice and in animals treated with ZnCl2 (stressed or non-stressed mice) and EAAC1 immunocontent was increased in stressed mice treated with ZnCl2, fluoxetine or vehicle and in non-stressed mice treated with ZnCl2 and fluoxetine. These findings indicate a robust effect of zinc in reversing behavioral alteration induced by CUS in mice, through a possible modulation of the glutamatergic neurotransmission, extending literature data regarding the mechanisms underlying its antidepressant-like action.

Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice.

Agmatine, an endogenous guanidine amine, has been shown to produce antidepressant-like effects in animal studies. This study investigated the effects of the combined administration of agmatine with either conventional monoaminergic antidepressants or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the tail suspension test (TST) in mice. The aim was to evaluate the extent of the antidepressant synergism by examining the ability of a fixed dose of agmatine to shift the antidepressant potency of fluoxetine, imipramine, bupropion and MK-801. A sub-effective dose of agmatine (0.0001 mg/kg, p.o.) significantly increased the potency by which fluoxetine, imipramine, bupropion and MK-801 decreased immobility time in the TST by 2-fold (fluoxetine), 10-fold (imipramine and bupropion) and 100-fold (MK-801). Combined with previous evidence indicating a role of monoaminergic systems in the effect of agmatine, the current data suggest that agmatine may modulate monoaminergic neurotransmission and augment the activity of conventional antidepressants. Moreover, this study found that agmatine substantially augmented the antidepressant-like effect of MK-801, reinforcing the notion that this compound modulates NMDA receptor activation. These preclinical data may stimulate future clinical studies testing the effects of augmentation therapy with agmatine for the management of depressive disorders.

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation.

Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1µg/site, PKA inhibitor), KN-62 (1µg/site, CAMKII inhibitor), chelerythrine (1µg/site, PKC inhibitor), PD98059 (5µg/site, MEK1/2 inhibitor), U0126 (5µg/site, MEK1/2 inhibitor), LY294002 (10nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1mg/kg, p.o.) and AR-A014418 (0.001µg/site, GSK-3ß inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3ß pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.