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1.
Biochim Biophys Acta Mol Basis Dis ; 1867(1): 165976, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33011198

RESUMO

BACKGROUND: There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia and dystonia share common biological pathways. We therefore aimed to increase our understanding of their shared pathophysiology by investigating their shared biological pathways and molecular networks. METHODS: We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology database and genome-wide association studies, and identified shared genes between the three diseases. We then assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression profiles and brain-tissue-specific gene co-expression networks. RESULTS: The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein-protein interaction networks. Biological processes common/shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic transmission, synaptic plasticity and nervous system development. The average expression of shared genes was significantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinct cerebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development. CONCLUSIONS: The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cerebellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing.


Assuntos
Ataxia , Encéfalo , Cerebelo , Depressão , Distonia , Plasticidade Neuronal , Transmissão Sináptica , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Depressão/genética , Depressão/metabolismo , Depressão/patologia , Distonia/genética , Distonia/metabolismo , Distonia/patologia , Estudo de Associação Genômica Ampla , Humanos , Mapas de Interação de Proteínas
2.
J Ethnopharmacol ; 264: 113281, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32810624

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The compatibility of Bupleurum chinense DC (Chaihu)-Paeonia lactiflora Pall (Baishao) is one of the most accepted herb pairs in traditional Chinese medicine (TCM) prescriptions for treating depression. However, the combination mechanisms of this herb pair for anti-depression remain unclear. MATERIALS AND METHODS: In this study, the combined effect of Chaihu-Baishao was evaluated by the chronic unpredictable mild stress (CUMS) rat model. Secondly, network pharmacology was constructed to dissect the united mechanisms. Based on the results of network pharmacology analysis, plasma metabolomics based on ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was performed to discover the collaborative effect on metabolite regulation. Furthermore, the targets from network pharmacology and the metabolites from metabolomics were jointly analyzed to select crucial metabolism pathways by MetaScape. Finally, the key metabolic enzymes and metabolites were experimentally validated by ELISA. RESULTS: The antidepressant effect of Chaihu-Baishao herb pair was significantly better than Chaihu or Baishao in sucrose preference test (SPT), open-field test (OFT), and forced swim test (FST). In network pharmacology, herb pair played synergetic effect through regulating shared pathways, such as MAPK signaling pathway and arachidonic acid metabolism, etc. Besides, by metabolomics, the herb pair improved more metabolites (14) than a single herb (10 & 9) and has a stronger regulation effect on metabolites. Correspondingly, herb pair adjusted more metabolism pathways (5) than individual herb (4 & 4). Furthermore, the arachidonic acid metabolism was selected as crucial metabolism pathways by a joint analysis of 199 targets and 14 metabolites. The results showed that herb pair regulated arachidonic acid metabolism by synergetic reducing the level of arachidonic acid, and inhibiting the enzyme activity of prostaglandin-endoperoxide synthase 1 (PTGS1) and prostaglandin-endoperoxide synthase 2 (PTGS2). CONCLUSIONS: This work provided an integrated strategy for revealing the combination mechanisms of Chaihu-Baishao herb pair for treating depression, and also a rational way for clarifying the composition rules of TCM.


Assuntos
Antidepressivos/uso terapêutico , Bupleurum , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolômica/métodos , Paeonia , Animais , Antidepressivos/isolamento & purificação , Depressão/metabolismo , Depressão/psicologia , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/isolamento & purificação , Masculino , Ratos , Ratos Sprague-Dawley
3.
J Stroke Cerebrovasc Dis ; 30(3): 105550, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33341564

RESUMO

BACKGROUND: Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action. METHODS: Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis. RESULTS: miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors. CONCLUSION: Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis.


Assuntos
Apoptose , Comportamento Animal , Região CA1 Hipocampal/metabolismo , Depressão/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Depressão/genética , Depressão/patologia , Depressão/psicologia , Modelos Animais de Doenças , Regulação para Baixo , Proteína 1 de Resposta de Crescimento Precoce/genética , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais
4.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374959

RESUMO

Previous studies suggest that depression may be associated with reactive oxygen species overproduction and disorders of the tryptophan catabolites pathway. Moreover, one-third of patients do not respond to conventional pharmacotherapy. Therefore, the study investigates the molecular effect of escitalopram on the expression of Cat, Gpx1/4, Nos1/2, Tph1/2, Ido1, Kmo, and Kynu and promoter methylation in the hippocampus, amygdala, cerebral cortex, and blood of rats exposed to CMS (chronic mild stress). The animals were exposed to CMS for two or seven weeks followed by escitalopram treatment for five weeks. The mRNA and protein expression of the genes were analysed using the TaqMan Gene Expression Assay and Western blotting, while the methylation was determined using methylation-sensitive high-resolution melting. The CMS caused an increase of Gpx1 and Nos1 mRNA expression in the hippocampus, which was normalised by escitalopram administration. Moreover, Tph1 and Tph2 mRNA expression in the cerebral cortex was increased in stressed rats after escitalopram therapy. The methylation status of the Cat promoter was decreased in the hippocampus and cerebral cortex of the rats after escitalopram therapy. The Gpx4 protein levels were decreased following escitalopram compared to the stressed/saline group. It appears that CMS and escitalopram influence the expression and methylation of the studied genes.


Assuntos
Encéfalo/efeitos dos fármacos , Citalopram/farmacologia , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Estresse Psicológico/fisiopatologia , Triptofano/metabolismo , Animais , Antidepressivos de Segunda Geração/farmacologia , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Doença Crônica , Depressão/genética , Depressão/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo , Estresse Oxidativo , Ratos Wistar , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
5.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322180

RESUMO

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.


Assuntos
Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Mycobacterium tuberculosis/metabolismo , Neurônios/patologia , Tuberculose Pulmonar/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/microbiologia , Sintomas Comportamentais/microbiologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/citologia , Encéfalo/enzimologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/microbiologia , Depressão/metabolismo , Depressão/microbiologia , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/citologia , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/patogenicidade , Neurônios/citologia , Neurotransmissores/metabolismo , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/psicologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Int J Mol Sci ; 21(24)2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33322800

RESUMO

In the present study, we aim to identify the effect of restrain stress (RS) on the expression of miRNAs in mouse serum. We used three genotypes of animals (mice with knock-out of the gene-encoding norepinephrine transporter, NET-KO; C57BL/6J, and SWR/J) which had previously been shown to display different sensitivity to RS, and focused on miRNAs which were altered by RS in the serum of all three genotypes. An analysis of miRNAs expression allowed for the identification of a set of 25 differentially expressed miRNAs; 10 were down-regulated compared to an appropriate control group of animals, while 15 were up-regulated. The application of DIANA-miRPath v. 3.0 allowed for the identification of selected pathways (KEGG) and Gene Ontology (GO) categories that were significantly controlled by these miRNAs, while miRWalk v. 3.0-the platform that used the machine learning based algorithm, TaRPmiR-was used to find their targets. The results indicate that 25 miRNAs, identified as altered upon RS in three genotypes of mice, are responsible for regulation of mRNA-encoding proteins that are key for the main hypotheses of depression; therefore, they may help to understand the link between stress and depression at the molecular level.


Assuntos
Depressão/metabolismo , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , MicroRNAs/sangue , Estresse Fisiológico/genética , Algoritmos , Animais , Depressão/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Ontologia Genética , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Restrição Física/fisiologia , Transdução de Sinais/genética , Regulação para Cima
7.
Artigo em Inglês | MEDLINE | ID: mdl-33031994

RESUMO

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.


Assuntos
Ansiedade/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Depressão/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Ansiedade/imunologia , Ansiedade/metabolismo , Ansiedade/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Depressão/imunologia , Depressão/metabolismo , Depressão/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Ácidos Graxos Ômega-3/imunologia , Ácidos Graxos Ômega-3/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
8.
PLoS One ; 15(10): e0239714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052909

RESUMO

The general public is increasingly aware of the role of genes in causing depression. Recent studies have begun uncovering unintended negative consequences of learning about a person's genetic susceptibility to disorders. Because people tend to believe that genes determine one's identity, having genes related to a disorder can be misinterpreted as equivalent to having the disorder. Consequently, learning that a person is genetically predisposed to depression can make people misremember mild depression as more severe. Participants across three experiments read a target vignette about a character displaying mild depressive symptoms, while descriptions of the character's genetic susceptibility to depression were experimentally manipulated. Participants then read a foil vignette describing a character with more severe depressive symptoms. Afterwards, participants who had learned that the target character was genetically predisposed to depression were comparatively more likely to misremember the target symptoms as being severe, when in fact they were mild. This pattern of results was obtained among both laypeople (Experiments 1 and 2) and practicing master's-level, but not doctoral-level, mental health clinicians (Experiment 3). Given that depression is diagnosed primarily based on a person's memory of depressive symptoms, the current findings suggest that genetic information about depression may lead to over-diagnosis of depression.


Assuntos
Depressão/genética , Predisposição Genética para Doença/psicologia , Testes Genéticos/ética , Adulto , Depressão/metabolismo , Depressão/psicologia , Transtorno Depressivo/psicologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Aprendizagem , Masculino , Memória , Preconceito/psicologia
9.
Medicine (Baltimore) ; 99(43): e22752, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120777

RESUMO

BACKGROUND: Electroacupuncture (EA) treatment has antidepressant effect and when patients were treated with EA and antidepressants, the effect could be maintained for a longer time. However, the effect of EA combined with antidepressants based on metabolism is still in the initial observation stage, which requires further research. METHODS: A total of 60 patients with moderate depression were assigned into 2 groups at a ratio of 1:1, the EA group (receiving EA and antidepressants) and the control group (taking antidepressants only) in this randomized controlled pilot trial. The EA treatment was performed 3 times a week for 8 consecutive weeks and then follow up for 4 weeks. The patients' depressive mood was measured by the Hamilton Depression scale (HAMD) at baseline, week 4, week 8 and week 12. Before and after 8-week treatment, morning urine samples from all patients were analyzed by the gas chromatography-mass spectrometry (GC-MS) to find possible metabolic markers of depression and of EA treatment related changes. RESULTS: Compared with the control group, the EA group showed more significant improvements in depressive symptoms measured by HAMD at week 4 (16.89 ±â€Š5.74 vs 25.58 ±â€Š7.03, P < .001), week 8 (9.59 ±â€Š5.13 vs 25.04 ±â€Š7.49, P < .001) and week 12 (11.07 ±â€Š6.85 vs 27.25 ±â€Š7.14, P < .001). The significant differences in urinary specific metabolites before and after EA treatment were malonic acid (fatty acid biosynthesis), cysteine (glutamate metabolism), glutathione (glutamate metabolism), tryptophan (tryptophan metabolism), proline (glutamate metabolism), and N-acetyl-5-hydroxytryptamine. These metabolites are involved in tryptophan metabolism, glutamate metabolism, and fatty acid biosynthesis. CONCLUSION: EA treatment combined with antidepressants is more effective in improving depressive symptoms than antidepressants alone. EA may treat depression by acting on tryptophan metabolism, glutamate metabolism, and fatty acid biosynthesis. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-2000030786.


Assuntos
Antidepressivos/uso terapêutico , Depressão/metabolismo , Depressão/terapia , Eletroacupuntura , Adulto , Correlação de Dados , Depressão/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
10.
Braz J Med Biol Res ; 53(10): e8826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901686

RESUMO

This study determined the expression of plasminogen activator inhibitor-1 (PAI-1) and microRNA (miR)-17 in a mouse depression model. Forty male mice were divided evenly into control and depression groups. A chronic unpredictable mild stress (CUMS) model was constructed. qRT-PCR was used to determine the expression of PAI-1 mRNA and miR-17. Western blotting and ELISA were used to determine expression of PAI-1 protein. Dual luciferase reporter assay was carried out to identify direct interaction between miR-17 and PAI-1 mRNA. The mice with depression had elevated PAI-1 mRNA and protein in hippocampal tissues and blood. Expression of miR-17 was decreased in hippocampal tissues and blood from mice with depression. miR-17 bound with the 3'-UTR of PAI-1 mRNA to regulate its expression. This study demonstrated that miR-17 expression in hippocampal tissues and blood from mice with depression was decreased while expression of PAI-1 mRNA and protein was up-regulated. miR-17 participated in depression in mice by regulating PAI-1.


Assuntos
Depressão/metabolismo , MicroRNAs , Inibidor 1 de Ativador de Plasminogênio , Animais , Hipocampo/metabolismo , Masculino , Camundongos , RNA Mensageiro
11.
Am J Psychiatry ; 177(10): 974-990, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32731813

RESUMO

OBJECTIVE: Microbiota dysbiosis has been linked to major depressive disorder, but the mechanisms whereby the microbiota modulates mood remain poorly understood. The authors tested whether specific changes in the microbiome modulate depressive-like behaviors. METHODS: Stools from learned helpless, non-learned helpless, and non-shocked mice were analyzed by V4 16S RNA sequencing to identify gut bacteria associated with learned helplessness and to quantify the level of the quorum-sensing molecule autoinducer-2 (AI-2). T cells were analyzed by flow cytometry, and serum amyloid proteins (SAA) were analyzed by quantitative real-time polymerase chain reaction. Fecal transfer approach and administration of oleic acid and AI-2 were used to determine the effects of the microbiome and quorum-sensing molecules on depressive-like behaviors. RESULTS: Mice deficient in segmented filamentous bacteria (SFB) were resilient to the induction of depressive-like behavior, and were resensitized when SFB was reintroduced in the gut. SFB produces the quorum-sensing AI-2 and promotes the production of SAA1 and SAA2 by the host, which increases T helper 17 (Th17) cell production. Th17 cells were required to promote depressive-like behaviors by AI-2, as AI-2 administration did not promote susceptibility to depressive-like behaviors or SAA1 and SAA2 production in Th17-deficient mice after stress. Oleic acid, an AI-2 inhibitor, exhibited antidepressant properties, reducing depressive-like behavior, intestinal SAA1 and SAA2 production, and hippocampal Th17 cell accumulation. Stool samples from 10 people with current depressive symptoms and 10 matched healthy control subjects were analyzed as well. Patients with current major depressive disorder exhibited increased fecal interleukin 17A, SAA, and SFB levels. CONCLUSIONS: The study results reveal a novel mechanism by which bacteria alter mood.


Assuntos
Depressão/metabolismo , Microbioma Gastrointestinal/fisiologia , Células Th17/fisiologia , Adulto , Animais , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Fezes/química , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/genética , Desamparo Aprendido , Humanos , Interleucina-17/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Percepção de Quorum , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteína Amiloide A Sérica/análise , Células Th17/metabolismo
12.
Life Sci ; 257: 118047, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629001

RESUMO

AIM: The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs). MATERIALS AND METHODS: To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining. KEY FINDINGS: We demonstrated that depression was improved after treatment with fluvoxamine. In addition, the prolongation of the corrected QT (QTc) interval under CMUS that increased vulnerability to VAs was significantly attenuated by stimulation of S1R due to the decreased amplitude of L-type calcium current (ICa-L) and the restoration of reduced transient outward potassium current (Ito) resulting from CMUS induction. The S1R also decelerated Ito inactivation and accelerated Ito recovery by activating Ca2+/calmodulin-dependent kinase II. Moreover, the stimulation of S1R ameliorated the structural remodeling as the substrate for maintenance of VAs. All these effects were abolished by the administration of S1R antagonist BD1047, which verified the roles for S1R. SIGNIFICANCE: Activation of S1R could decrease the vulnerability to VAs by inhibiting ICa-L and restoring Ito, in addition to ameliorating the CMUS-induced depressive symptoms and structural remodeling.


Assuntos
Depressão/metabolismo , Miócitos Cardíacos/metabolismo , Receptores sigma/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Fluvoxamina/metabolismo , Fluvoxamina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores sigma/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia
13.
Adv Pharmacol ; 89: 311-356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616212

RESUMO

Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Furey and Drevets in 2006 showed antidepressant response in patients after only a few doses with the antimuscarinic drug scopolamine. Several clinical reports have generally confirmed scopolamine as a rapid-acting antidepressant. The data with scopolamine are consistent with the adrenergic/cholinergic hypothesis of mania/depression derived from clinical reports originating in the 1970s from Janowsky and colleagues. Additional support for a role for muscarinic receptors in mood disorders comes from the greater efficacy of conventional antidepressants that have relatively high levels of muscarinic receptor blocking actions (e.g., the tricyclic antidepressant amitriptyline vs the selective serotonin reuptake inhibitor fluoxetine). There appears to be appreciable overlap in the mechanisms of action of scopolamine and other rapid-acting antidepressants (ketamine) or putative rapid-acting agents (mGlu2/3 receptor antagonists) although gaps exist in the experimental literature. Current hypotheses regarding the mechanisms underlying the rapid antidepressant response to scopolamine posit an M1 receptor subtype-initiated cascade of biological events that involve the amplification of AMPA receptors. Consequent impact on brain-derived neurotrophic factor and mTor signaling pathways result in the induction of dendritic spines that enable augmented functional connectivity in brain areas regulating mood. Two major goals for research in this area focus on finding ways in which scopolamine might best be utilized for depressed patients and the discovery of alternative compounds that improve upon the efficacy and safety of scopolamine.


Assuntos
Antidepressivos/farmacologia , Receptores Muscarínicos/metabolismo , Animais , Antidepressivos/química , Antidepressivos/uso terapêutico , Colina/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Humanos , Antagonistas Muscarínicos/uso terapêutico
14.
Proc Natl Acad Sci U S A ; 117(24): 13771-13782, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487727

RESUMO

The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN-specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.


Assuntos
Relógios Circadianos , Criptocromos/metabolismo , Depressão/metabolismo , Núcleo Accumbens/metabolismo , Animais , Comportamento Animal , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Dopamina/metabolismo , Feminino , Desamparo Aprendido , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo
15.
Psychopharmacology (Berl) ; 237(8): 2531-2545, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32488348

RESUMO

AIM: Indoleamine 2,3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in lipopolysaccharide (LPS)-treated mice and further explored its molecular mechanism by looking into the microglial kynurenine pathway. METHODS: To generate the model, LPS (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg, i.p.) 30 min before LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR, and ELISA. The TLR4/NF-κB signaling pathway and the expression of IDO, GluA2, and CamKIIß were also measured by western blotting. RESULTS: ASA VI exhibited significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhibited by ASA VI, which showed a dose-dependent pattern. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex caused by LPS administration. CONCLUSION: Our results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.


Assuntos
Antidepressivos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Saponinas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos/uso terapêutico , Células Cultivadas , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/psicologia , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , NF-kappa B/metabolismo , Saponinas/uso terapêutico , Receptor 4 Toll-Like/metabolismo
16.
Life Sci ; 257: 117991, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32569782

RESUMO

Traumatic brain injury (TBI) is a public health problem in which even though 80 to 90% of cases are considered mild, usually starts a sequence of neurological disorders that can last a considerable time. Most of the research of this injury has been focused on oxidative stress and functional deficits; however, mechanisms that underlie the development of neuropsychiatric disorders remain little researched. Due to this, the present authors decided to investigate whether recurrent concussion protocols alter depressive-like phenotype behavior, and whether mitochondria play an indispensable role in this behavior or not. The experimental data revealed, for the first time, that the present protocol of recurrent concussions (4, 7, and 10 injuries) in mice did not alter immobility time during tail suspension tests (TSTs), but decreased hippocampal mitochondrial respiration and increased expression of proteins such as nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide (SOD2). This experimental data suggests that bioenergetic changes elicited by recurrent concussion did not induce depressive-like behavior, but activated the transcription factor of responsive antioxidant elements (ARE) that delay or prevent secondary cascades in this neurological disease.


Assuntos
Concussão Encefálica/fisiopatologia , Depressão/metabolismo , Mitocôndrias/metabolismo , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Concussão Encefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Hipocampo/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo
17.
BMC Neurol ; 20(1): 250, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32563250

RESUMO

BACKGROUND: Post-stroke depression (PSD) is a mood disorder characterized by depression and anhedonia caused by stroke. Metabolomics identified metabolites associated with PSD, but previous studies are based on gas chromatography (GC)/mass spectrometry (MS). This study aimed to perform a liquid chromatography (LC)-MS-based metabolomics study of the plasma metabolite profiles between patients with PSD and controls. METHODS: This was a prospective study of patients with stroke enrolled between July and December 2017 at the Second Affiliated Hospital of Nanchang University. Patients were grouped as Hamilton Depression Rating Scale > 7 (PSD) or < 7 (controls). Metabonomics profiling of plasma sampled was conducted by LC-MS. By combining multivariable and univariable statistical analyses, significant differential metabolites between the two groups were screened. The threshold for significant differences was VIP ≥1 and P < 0.05. Log2FC is the logarithm of the mean ratio between the two groups. RESULTS: There were no significant difference with respect to age, NIHSS score, and MMSE between the two groups (all P > 0.05). There were six differential metabolites between the PSD and stroke groups, of which three metabolites were increased and three were decreased. Compared with the control group, p-chlorophenylalanine (Log2FC = 1.37, P = 0.03), phenylacetyl glutamine (Log2FC = 0.21, P = 0.048), and DHA (Log2FC = 0.77, P = 0.01) levels were higher in the PSD group, while betaine (trimethylglycine) (Log2FC = - 0.79, P = 0.04), palmitic acid (Log2FC = - 0.51, P = 0.001), and MHPG-SO4 (Log2FC = - 2.37, P = 0.045) were decreased. CONCLUSION: Plasma metabolomics showed that amino acid metabolism (phenylacetyl glutamine, p-chlorophenylalanine, trimethylglycine), lipid metabolism (DHA, palmitic acid, trimethylglycine), and oxidative stress (DHA, palmitic acid, trimethylglycine) were associated with PSD. These results could help to reveal the pathophysiological mechanism of PSD and eventually identify treatment targets.


Assuntos
Aminoácidos/metabolismo , Depressão/metabolismo , Metabolismo dos Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Acidente Vascular Cerebral/complicações , Idoso , Depressão/etiologia , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/psicologia
18.
Psychiatry Res ; 291: 113198, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32535509

RESUMO

An option currently being explored for the treatment of COVID-19 is the use of interferons (INFs), either alone or in combination with other antiviral agents. INFs are known to shift the metabolism of tryptophan (TRP) away from its role as a precursor of serotonin. For some patients, reduction in TRP levels may either expose an underlying vulnerability to depression or trigger a de novo episode of depression. This Commentary discusses the pathway involved and recommends in-hospital augmentation with foods or supplements that increase TRP levels for COVID-19 patients treated with INFs. Selective serotonin reuptake inhibitors may also be tried if the depressive symptomatology is not short-lived.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/psicologia , Depressão/metabolismo , Interferons/metabolismo , Pneumonia Viral/metabolismo , Pneumonia Viral/psicologia , Depressão/psicologia , Humanos , Pandemias , Serotonina/metabolismo , Triptofano/metabolismo
19.
Psychopharmacology (Berl) ; 237(8): 2517-2530, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445053

RESUMO

RATIONALE: Major depression is a serious, but common, psychological disorder, which consists of a long-lasting depressive mood, feelings of helplessness, anhedonia, and sleep disturbances. It has been reported that rats with bilateral olfactory bulbectomies (OBXs) exhibit depressive-like behaviors which indicates that the olfactory bulb (OB) plays an important role in the formation of depression. However, which type of OB neurons plays an important role in the formation of depression remains unclear. OBJECTIVE: To determine the role of OB neuronal types in depression and related sleep-wake dysfunction. METHODS: Firstly, we established and evaluated a conventional physical bilateral OBX depression model. Secondly, we used chemical methods to ablate OB neurons, while maintaining the original shape, and evaluated depressive-like behaviors. Thirdly, we utilized AAV-flex-taCasp3-TEVp and transgenetic mice to specifically ablate the OB GABAergic or glutamatergic neurons, then evaluated depressive-like behaviors. RESULTS: Compared with measured parameters in sham mice, mice with OBXs or ibotenic acid-induced OB lesions exhibited depressive-like behaviors and sleep disturbances, as demonstrated by results of depressive-like behavior tests and sleep recordings. Selective lesioning of OB glutamatergic neurons, but not GABAergic neurons induced depressive-like behaviors and increased rapid eye movement sleep during the light phase of the circadian cycle. CONCLUSIONS: These results indicate that OB glutamatergic neurons play a key role in olfactory-related depression and sleep disturbance.


Assuntos
Depressão/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/metabolismo , Bulbo Olfatório/cirurgia , Transtornos do Sono-Vigília/metabolismo , Técnicas de Ablação/métodos , Animais , Depressão/induzido quimicamente , Depressão/psicologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Ibotênico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição Aleatória , Sono/efeitos dos fármacos , Sono/fisiologia , Transtornos do Sono-Vigília/induzido quimicamente
20.
Psychopharmacology (Berl) ; 237(8): 2547-2553, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445055

RESUMO

BACKGROUND: Although glutamate transmission via astrocytes has been proposed to contribute to the pathophysiology of depression, the precise mechanisms are unknown. Herein, we investigated the levels of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) of astrocytes in learned helplessness (LH) rats (an animal model of depression) and non-LH rats (an animal model of resilience). METHODS: We administered inescapable mild electric shock to rats and then discriminated the LH and non-LH rats by a post-shock test. Almost 55% of the rats acquired LH. We then measured the expressions of GLT-1 and GS in several brain regions of LH and non-LH rats by Western blot analysis. RESULTS: The levels of GLT-1 and GS in the CA-1, CA-3, dentate gyrus (DG), medial prefrontal cortex (mPF), and nucleus accumbens (NAc) of the LH group were significantly higher than those of the control group. The GS levels in the amygdala of the LH rats were significantly decreased compared to the controls. There were significant differences in GLT-1 and GS levels between the non-LH and LH rats in the CA-1 and CA-3. CONCLUSIONS: These results suggest that the LH rats experienced up-regulations of GLT-1 and GS in the CA-1, CA-3, DG, mPF, and NAc and a down-regulation of GS in the amygdala. It is possible that the effects of the GLT-1 and GS levels on astrocytes in the CA-1 and CA-3 are critical for the differentiation of resilience from vulnerability.


Assuntos
Encéfalo/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Transportador de Glucose Tipo 1/metabolismo , Glutamato-Amônia Ligase/metabolismo , Desamparo Aprendido , Animais , Masculino , Ratos , Ratos Sprague-Dawley
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