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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Serotonergic and noradrenergic systems are implicated in the antidepressant-like effect of ursolic acid in mice.

Ursolic acid (UA) is a natural pentacyclic triterpenoid carboxylic acid that exerts antidepressant-like effects in the tail suspension test (TST) and in the forced swimming test, and this effect was reported to be mediated by the dopaminergic system. Many studies show that currently available antidepressant agents have effects on multiple neurotransmitter systems which account for their efficacy. Therefore, this study was aimed at investigating the possible involvement of the serotonergic, noradrenergic, glutamatergic and opioid systems in the antidepressant-like effect of UA. To this end, several pharmacological agents were administered to verify their ability to influence the antidepressant-like responses elicited by UA in the TST in mice. The open-field test was used to assess the locomotor activity. The results show that the pre-treatment of mice with ρ-chlorophenylalanine (100mg/kg, i.p., 4 days) or α-methyl-ρ-tyrosine (100mg/kg, i.p.) but not with N-methyl-d-aspartate (0.1 pmol/mouse, i.c.v.) or naloxone (1mg/kg, i.p.), was able to prevent the antidepressant-like effect of UA (0.1mg/kg, p.o.). Sub-effective doses of fluoxetine (5mg/kg, p.o.) or reboxetine (2mg/kg, p.o.), but not ketamine (0.1mg/kg, i.p.) or MK-801 (0.001 mg/kg, p.o.), was capable of potentiating the effect of a sub-effective dose of UA (0.001 mg/kg, p.o.) in the TST. None of the treatments affected locomotor activity. Altogether, the results show an involvement of the serotonergic and noradrenergic systems, but not the glutamatergic or opioid systems, in the antidepressant-like effect of UA.

Nutritional strategies for dealing with depression.

Depression is a highly recurrent and debilitating psychiatric disorder associated with multicausal origins. Impairments in the monoaminergic transmission, increased glutamatergic excitotoxicity, neuroinflammation, oxidative stress and deficits in neurotrophic factors are the main hypothesis raised in order to explain the etiological basis of depression. Although the current antidepressant therapy usually alleviates symptoms and prevents recurrence of episodes, the delay in the onset of the therapeutic effect and the refractory or intolerant responses exhibited by a large number of patients are the main drawbacks of the current therapy. For these reasons, several studies have dealt with the investigation of alternative therapeutic approaches or adjunctive strategies which could improve clinical outcomes. One potential adjunctive treatment with conventional antidepressants involves the use of nutraceuticals (a food, a part of a food, a vitamin, a mineral, or a herb that provides health benefits). In this review, we will focus on the main nutrients, phytochemicals and food that have been shown to have beneficial effects against depression.

Antidepressant-like effect of α-tocopherol in a mouse model of depressive-like behavior induced by TNF-α.

Taking into account that pro-inflammatory cytokines and oxidative and nitrosative stress are implicated in the pathogenesis of depression and that α-tocopherol has antidepressant, anti-inflammatory and antioxidant properties, this study investigated the ability of α-tocopherol to abolish the depressive-like behavior induced by i.c.v. administration of TNF-α in the mouse TST. Additionally, we investigated the occurrence of changes in the levels of Bcl2 and Bax and phosphorylation of GSK-3ß (Ser9) in the hippocampus of mice. The administration of TNF-α (0.001fg/site, i.c.v.) increased the immobility time in the TST, which was prevented by the administration of α-tocopherol at the doses of 10, 30 and 100mg/kg (p.o.). Subeffective doses of α-tocopherol (10mg/kg, p.o.) and/or the antidepressants fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.) and bupropion (1mg/kg, p.o.), the NMDA receptor antagonist MK-801 (0.001mg/kg, p.o.) or the neuronal nitric oxide synthase inhibitor 7-nitroindazole (25mg/kg, i.p.) prevented the depressive-like effect induced by TNF-α. None of the treatments altered the locomotor activity of mice. Treatment with TNF-α and/or α-tocopherol did not alter the levels of Bax and Bcl2 or the phosphorylation of GSK-3ß in the hippocampus of mice. Together, our results show a synergistic antidepressant-like effect of α-tocopherol with antidepressants against the depressive-like behavior induced by an inflammatory insult, suggesting that this vitamin may be useful to optimize conventional pharmacotherapy of depression, including depressive states associated with inflammatory conditions.