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1.
Sheng Li Xue Bao ; 74(2): 165-176, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35503064

RESUMO

This paper was aimed to clarify the effect of high-intensity interval training (HIIT) on depression. Animal running platforms were used to establish HIIT exercise models, depression models were prepared by chronic unpredictable mild stress (CUMS), and depression-related behaviors were detected by behavioral experiments. The results showed that HIIT exercise improved depression-related behavior in CUMS model mice. Western blot and ELISA results showed that in the hippocampus, medial prefrontal cortex (mPFC) and amygdala of the CUMS model mice, glucocorticoid receptor (GR) protein expression was down-regulated, and the content of tumor necrosis factor α (TNF-α) was increased, compared with those in the control group, whereas HIIT exercise could effectively reverse these changes in CUMS model mice. These results suggest that HIIT exercise can exert antidepressant effect, which brings new ideas and means for the clinical treatment of depressive diseases.


Assuntos
Depressão , Estresse Psicológico , Animais , Antidepressivos/farmacologia , Comportamento Animal , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Estresse Psicológico/tratamento farmacológico
2.
Stem Cells ; 40(1): 59-73, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35511865

RESUMO

Increased neurogenesis elicits antidepressive-like effects. The antidiabetic drug metformin (Met) reportedly promotes hippocampal neurogenesis, which ameliorates spatial memory deficits and depression-like behaviors. However, the precise molecular mechanisms underpinning Met-induced neuronal differentiation of neural stem cells (NSCs) remain unclear. We showed that Met enhanced neuronal differentiation of NSCs via Gadd45g but not Gadd45a and Gadd45b. We further found that Gadd45g increased demethylation of neurogenic differentiation 1 promoter by regulating the activity of passive and active DNA demethylation enzymes through an adenylate-activated protein kinase -independent mechanism in Met-treated NSCs. Importantly, genetic deficiency of Gadd45g decreased hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors in the adult mice, whereas forced expression of Gadd45g alleviated the depressive-like behaviors. Our findings provide a model that Gadd45g-mediated DNA demethylation contributes to Met-induced neuronal genesis and its antidepressant-like effects and propose the concept that targeting Gadd45g regulation of neurogenesis might serve as a novel antidepressant strategy.


Assuntos
Metformina , Células-Tronco Neurais , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Desmetilação do DNA , Hipocampo/metabolismo , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Células-Tronco Neurais/metabolismo , Neurogênese
3.
Biol Pharm Bull ; 45(4): 538-541, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370281

RESUMO

Several studies have proposed δ opioid receptors as influential targets for developing novel antidepressants. Deltorphin (DLT) and deltorphin II (DLT-II) have high affinity and selectivity for δ opioid receptors; thus, it is likely that DLT analogs possess antidepressant-like effects. Based on this, we evaluated the effects of four DLT analogs (DLT-related synthetic peptides) on immobility behavior in the tail suspension test. Intracerebroventricular administration of DLT or [N-isobutyl-Gly6]DLT in mice significantly decreased immobile behavior. However, administration of DLT did not affect locomotor activity, whereas that of [N-isobutyl-Gly6]DLT significantly increased locomotion in mice. The effect of the shortened immobility time following DLT administration was counteracted by the administration of the selective δ1 opioid receptor antagonist 7-benzylidenenaltrexone, but not by the selective δ2 opioid receptor antagonist naltriben. These findings suggest that DLT has an antidepressant-like effect by activating the central δ1 opioid receptor in mice.


Assuntos
Elevação dos Membros Posteriores , Receptores Opioides delta , Animais , Antidepressivos/farmacologia , Camundongos , Antagonistas de Entorpecentes/farmacologia , Oligopeptídeos
4.
Drug Des Devel Ther ; 16: 843-861, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370402

RESUMO

Background: There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study. Objective: This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd. Methods: In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors. Results: Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2. Conclusion: Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.


Assuntos
Roedores , Fator A de Crescimento do Endotélio Vascular , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Ginsenosídeos , Camundongos , Simulação de Acoplamento Molecular , Ratos , Roedores/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Riv Psichiatr ; 57(2): 57-66, 2022.
Artigo em Italiano | MEDLINE | ID: mdl-35426424

RESUMO

About a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatment, i.e., develop a treatment-resistant depression (TRD). The partial understanding of MDD pathophysiology currently constitutes the major barrier to clinical and research progress on this topic. However, recent advances in genome editing techniques as well as in induced pluripotent stem cells (iPSC) technology are offering unprecedented opportunities in both human disease modelling and drug discovery. These technology progresses have been enabling to set up disease-relevant patient-specific in vitro disease modeling for various mental disorders. The resulting models have the potential to significantly improve pathophysiologic understanding of MDD and then overcome some limitations inherent to animal and post-mortem models. More recently, psychiatry started to deal with the fast acting antidepressant ketamine and its derivates. Although ketamine appears to have the potential to transform the treatment of depression, its specific mechanisms of action are only partially known. Such knowledge is necessary to develop a model to understand the mechanisms behind fast-acting antidepressants, which may enable the discovery of novel glutamatergic compounds for the treatment of MDD. After discussing both the current understanding of ketamine's mechanisms of action, and the state of the art of human iPSC technology, the authors will introduce the implementation of a TRD model based on iPSC human technology and aimed at studying the ketamine's fast acting antidepressant mechanisms of action.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico
6.
J Affect Disord ; 309: 201-210, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35461819

RESUMO

BACKGROUND: Current pharmaceutical treatments for depression are sometimes ineffective and may have unwanted side effects that interfere with patient compliance. This study examined the potential antidepressant-like effects of dietary- and microbial-derived aryl hydrocarbon receptor (AhR) ligands, 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA). METHODS: Female C57BL/6 mice were subjected to unpredictable chronic mild stress (UCMS) or were unstressed. For three weeks prior to UCMS mice were fed daily with vehicle or 20 mg/kg DIM, 1,4-DHNA or AhR-inactive isomer 3,7-DHNA; another group was subjected to two weeks UCMS before ligand administration began. Mice were examined for anhedonia-like behavior as measured by the sucrose preference test. Additionally, anxiety levels of the mice were examined before UCMS and ligand administration began and at the end in the open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests. At the end of the experiment they were also examined in the Morris water maze (MWM) task. RESULTS: Both DIM and 1,4-DHNA, but not 3,7-DHNA, successfully prevented and reversed UCMS-induced anhedonia-like behavior. Furthermore, both DIM and DHNA had little to no effect on anxiety levels and did not induce spatial learning deficits. LIMITATIONS: Additional studies are required to determine to what degree the antidepressant-like effects of DIM and 1,4-DHNA can be attributed to their activities as AhR ligands. CONCLUSIONS: Our findings indicate that dietary and microbial-derived AhR ligands may have clinical applications as potential antidepressants. Future studies are necessary to elucidate the role of AhR in depression-like states and the underlying mechanisms of action.


Assuntos
Anedonia , Antidepressivos , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Feminino , Humanos , Indóis , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Naftóis , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico
7.
Int J Mol Sci ; 23(7)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35409171

RESUMO

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.


Assuntos
COVID-19 , Fluvoxamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , COVID-19/tratamento farmacológico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Humanos , Pandemias , SARS-CoV-2 , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico
8.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409234

RESUMO

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-ß, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.


Assuntos
Transtorno Depressivo Maior , MicroRNAs , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Mirtazapina/uso terapêutico , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico
9.
Nat Med ; 28(4): 844-851, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35411074

RESUMO

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck's depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo ('psilocybin arm') or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) ('escitalopram arm'). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.


Assuntos
Transtorno Depressivo Maior , Alucinógenos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo/diagnóstico por imagem , Depressão/diagnóstico por imagem , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Alucinógenos/uso terapêutico , Humanos , Psilocibina/farmacologia , Psilocibina/uso terapêutico
10.
Molecules ; 27(7)2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35408500

RESUMO

Depression is the most common mental illness, affecting approximately 4.4% of the global population. Despite many available treatments, some patients exhibit treatment-resistant depression. Thus, the need to develop new and alternative treatments cannot be overstated. Adenosine receptor antagonists have emerged as a promising new class of antidepressants. The current study investigates a novel dual A1/A2A adenosine receptor antagonist, namely 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1H-inden-1-one (1a), for antidepressant capabilities by determining its metabolic profiles and comparing them to those of two reference compounds (imipramine and KW-6002). The metabolic profiles were obtained by treating male Sprague-Dawley rats with 1a and the reference compounds and subjecting them to the forced swim test. Serum and brain material was consequently collected from the animals following euthanasia, after which the metabolites were extracted and analyzed through untargeted metabolomics using both 1H-NMR and GC-TOFMS. The current study provides insight into compound 1a's metabolic profile. The metabolic profile of 1a was similar to those of the reference compounds. They potentially exhibit their antidepressive capabilities via downstream effects on amino acid and lipid metabolism.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Antagonistas de Receptores Purinérgicos P1 , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Humanos , Masculino , Metabolômica , Nucleosídeos de Purina , Ratos , Ratos Sprague-Dawley
11.
Molecules ; 27(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35408607

RESUMO

In this study, the attenuative effects of the hydro-alcoholic extract from Mitragyna speciosa (MSE) against diabetes-induced anxiety and depression-like behaviors were examined. In addition, UPLC/ESI/TOF-MS analysis was performed to identify the phytochemical nature of MSE. DM was induced using a combination of high fructose/streptozotocin, and the diabetic rats were treated with MSE (50 and 200 mg/kg) for 5 weeks. After treatment, the animals were subjected to a forced swim test, open field test and elevated plus-maze tests. Additionally, proinflammatory cytokines and oxidative stress parameters were evaluated in the brain tissues of the rats. UPLC/ESI/TOF-MS analysis revealed that MSE is abundantly rich in polyphenolic constituents, notably flavonoid and phenolic glycosides. Behavioral tests and biochemical analyses indicated that diabetic rats showed significantly increased anxiety and depressive-like behavioral deficits, brain oxidative stress and pro-inflammatory cytokines levels (IL-1ß, IL-6 and TNF-α). Treatment with MSE (50 and 200 mg/kg) significantly attenuated increased blood glucose level, depressive and anxiety-like behaviors in diabetic rats. Additionally, the antioxidant enzymes activities were markedly increased in MSE-treated animals, while TNF-α, IL-1ß and IL-6 cytokines were notably suppressed. Taken together, these results suggested that MSE has potentials as antidepressant and anxiolytic-like effects and improves the brain oxido-inflammatory status in diabetic rats.


Assuntos
Ansiolíticos , Diabetes Mellitus Experimental , Mitragyna , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Comportamento Animal , Citocinas , Diabetes Mellitus Experimental/tratamento farmacológico , Interleucina-6/farmacologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Fator de Necrose Tumoral alfa/farmacologia
12.
Neuropsychopharmacol Hung ; 24(1): 17-28, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35451589

RESUMO

Prescribing antidepressant medication is currently the most effective way of treating major depression, but only very few patients achieve permanent improvement. Therefore, it is important to identify objectively measurable markers for effective, personalized therapy. The aim of this review article is to collect all the markers that are robustly predictive of the outcome of therapy. We searched for systematic review articles that have simultaneously investigated the effects of as many different markers as possible on the response to antidepressant therapy in major depressive patients. From these we extracted markers that have been found to be significant by at least two independent review studies and that have proven replicable also within each of these reviews. A separate search was performed for meta-analyses of pharmacogenetic genome-wide association studies. Based on our results, onset time, symptom severity, presence of anhedonia, early treatment response, comorbid anxiety, alcohol consumption, frontal EEG theta activity, hippocampal volume, activity of anterior cingulate cortex, as well as a peripheral marker, serum BDNF levels have proven replicable predictors of antidepressant response. Pharmacogenomic studies to date have not yielded replicable results. Predictors identified as robust by our study may provide a starting point for future machine learning models within a 'big data' database of major depressive patients. (Neuropsychopharmacol Hung 2022; 24(1): 17-28).


Assuntos
Transtorno Depressivo Maior , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Big Data , Transtorno Depressivo Maior/tratamento farmacológico , Estudo de Associação Genômica Ampla , Humanos
13.
Stress ; 25(1): 145-155, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35384793

RESUMO

Worldwide, millions of people suffer from treatment-resistant depression. Ketamine, a glutamatergic receptor antagonist, can have a rapid antidepressant effect even in treatment-resistant patients. A proposed mechanism for the antidepressant effect of ketamine is the reduction of neuroinflammation. To further explore this hypothesis, we investigated whether a single dose of ketamine can modulate protracted neuroinflammation in a repeated social defeat (RSD) stress rat model, which resembles features of depression. To this end, male animals exposed to RSD were injected with ketamine (20 mg/kg) or vehicle. A combination of behavioral analyses and PET scans of the inflammatory marker TSPO in the brain were performed. Rats submitted to RSD showed anhedonia-like behavior in the sucrose preference test, decreased weight gain, and increased TSPO levels in the insular and entorhinal cortices, as observed by [11C]-PK11195 PET. Whole brain TSPO levels correlated with corticosterone levels in several brain regions of RSD exposed animals, but not in controls. Ketamine injection 1 day after RSD disrupted the correlation between TSPO levels and serum corticosterone levels, but had no effect on depressive-like symptoms, weight gain or the protracted RSD-induced increase in TSPO expression in male rats. These results suggest that ketamine does not exert its effect on the hypothalamic-pituitary-adrenal axis by modulation of neuroinflammation.


Assuntos
Anedonia , Ketamina , Animais , Antidepressivos/farmacologia , Proteínas de Transporte , Corticosterona , Depressão/metabolismo , Depressão/prevenção & controle , Modelos Animais de Doenças , Sistema Hipotálamo-Hipofisário/metabolismo , Ketamina/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de GABA/metabolismo , Receptores de GABA-A , Estresse Psicológico/metabolismo , Ganho de Peso
14.
J Clin Psychopharmacol ; 42(3): 284-292, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35420565

RESUMO

PURPOSE/BACKGROUND: Studies for repurposed drugs in severe acute respiratory syndrome coronavirus type 2-infected and coronavirus disease 2019 (COVID-19) patients are ongoing. According to preclinical research, antidepressants (ADs) might be useful in the treatment of COVID-19. METHODS/PROCEDURES: We conducted a scoping review including clinical studies on AD effects on SARS-CoV-2 infection and COVID-19. FINDING/RESULTS: As of January 2, 2022, we found 14 clinical studies, which could be included into this review. Among them, there were 2 randomized, placebo-controlled studies and 2 prospective parallel-group studies about the efficacy/effectiveness and tolerability of fluvoxamine. The remaining studies were mainly retrospective studies considering COVID-19 hospital populations predominantly exposed to fluoxetine (N = 3), other selective serotonin reuptake inhibitors (SSRI), selective norepinephrine reuptake inhibitors (SNRI), and trazodone. The vast majority were hospital studies and assessed COVID-19 severity (morbidity) and mortality as primary endpoints. The only outpatient study (fluvoxamine) investigated the COVID-19-related hospitalization rate, and 1 psychiatric hospital study (SSRI, SNRI, trazodone) focused on the SARS-CoV-2 infection rate. IMPLICATIONS/CONCLUSIONS: At present, the best evidence of an "anti-COVID-19" potential of ADs exists for fluvoxamine and, to a lesser extent, for fluoxetine. Preliminary evidence had found that patients exposed to SSRI or SNRI substance classes might have a reduced mortality risk and that trazodone might reduce SARS-CoV-2 infection rates. Three studies found no relevant influence of ADs on COVID-19 morbidity and mortality, and 1 study described increased mortality. The latter study, however, did not differentiate between psychotropic medication and ADs. Tricyclics and monoamine oxidase inhibitors are still absolute "dark zones" in COVID-19 research. Further controlled studies testing the effectiveness/efficacy and tolerability/safety (as well as the treatment timing and duration) of different AD substance classes in COVID-19 and post/long-COVID patients of various populations are warranted.


Assuntos
COVID-19 , Inibidores da Recaptação de Serotonina e Norepinefrina , Trazodona , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , COVID-19/complicações , COVID-19/tratamento farmacológico , Fluoxetina/farmacologia , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Humanos , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2 , Inibidores de Captação de Serotonina/efeitos adversos
15.
ACS Chem Neurosci ; 13(8): 1129-1142, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35348335

RESUMO

G-protein coupled receptors (GPCRs) are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5 as is the case for the related adrenergic receptors? Studying vortioxetine (VXT), an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of VXT binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare it with available experimental data. We are able to rationalize the differential mode of action of VXT at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation that inform about an activation mechanism that does not involve polar interaction with helix 5. The results extend our current understanding of agonist and antagonist action at aminergic GPCRs.


Assuntos
Piperazinas , Serotonina , Antidepressivos/farmacologia , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G , Serotonina/metabolismo , Vortioxetina/farmacologia
16.
J Ethnopharmacol ; 292: 115218, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35337919

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years. AIM OF THE STUDY: LBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron. MATERIALS AND METHODS: In this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and Western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization. RESULTS: In the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144-3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144-3p expression. CONCLUSIONS: These findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144-3p mediated GABA synthesis and release.


Assuntos
Lilium , MicroRNAs , Rehmannia , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Hibridização in Situ Fluorescente , Interneurônios/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Somatostatina , Peptídeo Intestinal Vasoativo/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Sci Rep ; 12(1): 3647, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35256610

RESUMO

Dittrichia viscosa is a perennial Mediterranean plant used in traditional medicine for "calming purposes", pointing at a possible antidepressant activity of the plant. We conducted chromatographic and bioassay-guided fractionation of D. viscosa root extract to isolate a specific fraction (fraction "K") with antidepressant-like characteristics in vivo and strong antioxidant properties in vitro. A single dose of "K" reduced immobility time in the forced swim test with a mouse model possessing a depressive-like phenotype. Neurochemical profiling for 5-hydroxytryptamine (5-HT) and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in prefrontal cortex and hippocampus of "K"-treated mice showed reduction in 5-HIAA, indicative of either serotonin uptake transporter or monoamine oxidase-A inhibition, as well as slight increases in 5-HT content. These neurochemical alterations, as well as the behavioral changes observed, were comparable to the effects of paroxetine. "K" also protected PC12 cells in a H2O2 cytotoxicity assay, thus demonstrating antioxidant properties, yet paroxetine augmented oxidative damage and cell death. Identification of the main compounds in "K" by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) indicated that chlorogenic acid and cynarine comprised 87% of the total components. D. viscosa root extract appears to produce antidepressant and cytoprotective effects and may serve as an attractive alternative to standard therapies for depression.


Assuntos
Asteraceae , Ácido Clorogênico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antioxidantes/farmacologia , Asteraceae/química , Comportamento Animal , Ácido Clorogênico/farmacologia , Cinamatos , Peróxido de Hidrogênio/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Camundongos , Paroxetina , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina , Espectrometria de Massas em Tandem
18.
BMC Psychiatry ; 22(1): 218, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35337298

RESUMO

BACKGROUND: Most antidepressants have been developed on the basis of the monoamine deficiency hypothesis of depression, in which neuronal serotonin (5-HT) plays a key role. 5-HT biosynthesis is regulated by the rate-limiting enzyme tryptophan hydroxylase-2 (TPH2). TPH2 methylation is correlated with antidepressant effects. Resting-state functional MRI (rs-fMRI) is applied for detecting abnormal brain functional activity in patients with different antidepressant effects. We will investigate the effect of the interaction between rs-fMRI and TPH2 DNA methylation on the early antidepressant effects. METHODS: A total of 300 patients with major depressive disorder (MDD) and 100 healthy controls (HCs) were enrolled, of which 60 patients with MDD were subjected to rs-fMRI. Antidepressant responses was assessed by a 50% reduction in 17-item Hamilton Rating Scale for Depression (HAMD-17) scores at baseline and after two weeks of medication. The RESTPlus software in MATLAB was used to analyze the rs-fMRI data. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), fractional ALFF (fALFF), and functional connectivity (FC) were used, and the above results were used as regions of interest (ROIs) to extract the average value of brain ROIs regions in the RESTPlus software. Generalized linear model analysis was performed to analyze the association between abnormal activity found in rs-fMRI and the effect of TPH2 DNA methylation on antidepressant responses. RESULTS: Two hundred ninety-one patients with MDD and 100 HCs were included in the methylation statistical analysis, of which 57 patients were included in the further rs-fMRI analysis (3 patients were excluded due to excessive head movement). 57 patients were divided into the responder group (n = 36) and the non-responder group (n = 21). Rs-fMRI results showed that the ALFF of the left inferior frontal gyrus (IFG) was significantly different between the two groups. The results showed that TPH2-1-43 methylation interacted with ALFF of left IFG to affect the antidepressant responses (p = 0.041, false discovery rate (FDR) corrected p = 0.149). CONCLUSIONS: Our study demonstrated that the differences in the ALFF of left IFG between the two groups and its association with TPH2 methylation affect short-term antidepressant drug responses.


Assuntos
Mapeamento Encefálico , Transtorno Depressivo Maior , Triptofano Hidroxilase , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Metilação de DNA , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética/métodos , Serotonina , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/uso terapêutico
19.
BMC Psychiatry ; 22(1): 182, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35291971

RESUMO

BACKGROUND: Preclinical studies have indicated that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of (2R,6R)-HNK in a chronic restraint stress (CRS) mouse model. METHODS: C57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering (2R,6R)-HNK (10 mg/kg), a combination of (2R,6R)-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of (2R,6R)-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT-PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio. RESULTS: (2R,6R)-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, (2R,6R)-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of (2R,6R)-HNK were blocked by combinations with NBQX or ANA-12. CONCLUSION: BDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of (2R,6R)-HNK in the CRS model of depression.


Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Proteína C-Reativa , Depressão , Ketamina , Proteínas do Tecido Nervoso , Receptor trkB , Animais , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína C-Reativa/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ketamina/análogos & derivados , Ketamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Receptor trkB/metabolismo , Regulação para Cima
20.
J Sep Sci ; 45(10): 1656-1671, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35234356

RESUMO

Baihe-Dihuang Tang is a commonly prescribed remedy for depression. In this study, component screening with untargeted and targeted metabolomics was used to identify potential biomarkers for depression in chronic unpredictable mildly stressed rats. Using this novel identification method, the screening of organic acids, lily saponins, iridoids, and other ingredients formed the basis for subsequent metabolomics research. Baihe-Dihuang Tang supplementation in chronic unpredictable mild-stress-induced depression models, increased their body weight, sucrose preference, brain-derived neurotrophic factor deposition, and spatial exploring. Untargeted metabolomics revealed that Baihe-Dihuang Tang exerts its antidepressant effects by regulating the levels of lipids, organic acids, and its derivatives, and benzenoids in the brain, plasma, and urine of the depressed rats. Moreover, it also modulates the d-glutamine and d-glutamate metabolism and purine metabolism. Targeted metabolomics demonstrated significant reduction in l-glutamate levels in the brains of depressed rats. This could be a potential biomarker for depression. Baihe-Dihuang Tang alleviated depression by regulating the levels of l-glutamate, xanthine, and adenine in the brains of depressed rats. Together, these findings conclusively established the promising therapeutic effect of Baihe-Dihuang Tang on depression and also unraveled the underlying molecular mechanism of its potential antidepressant function.


Assuntos
Depressão , Medicamentos de Ervas Chinesas , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Biomarcadores , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ácido Glutâmico/metabolismo , Metabolômica/métodos , Ratos
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