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1.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360852

RESUMO

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.


Assuntos
Antidepressivos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Fluoxetina/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Ácidos Graxos Insaturados/metabolismo , Macaca mulatta , Masculino
2.
Prog Mol Biol Transl Sci ; 173: 61-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32711818

RESUMO

Highly complex endophenotypes and underlying molecular mechanisms have prevented effective diagnosis and treatment of autism spectrum disorder. Despite extensive studies to identify relevant biosignatures, no biomarker and therapeutic targets are available in the current clinical practice. While our current knowledge is still largely incomplete, -omics technology and machine learning-based big data analysis have provided novel insights on the etiology of autism spectrum disorders, elucidating systemic impairments that can be translated into biomarker and therapy target candidates. However, more integrated and sophisticated approaches are vital to realize molecular stratification and individualized treatment strategy. Ultimately, systemic approaches based on -omics and big data analysis will significantly contribute to more effective biomarker and therapy development for autism spectrum disorder.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/terapia , Biomarcadores/metabolismo , Análise de Dados , Genômica , Proteômica , Transcriptoma/genética , Humanos , Terapia de Alvo Molecular
3.
Front Psychiatry ; 11: 518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581888

RESUMO

Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.

4.
J Psychiatr Res ; 129: 8-14, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32540574

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are the predominant drugs prescribed for Major Depressive Disorder. The immediate pharmacological target of SSRIs is the serotonin transporter. However, the delayed therapeutic effect and high rate of patient non-response make it highly likely that SSRIs also have other molecular targets that are yet to be identified. Cellular thermal shift assay (CETSA) is a method based on thermal stabilization of target proteins upon drug binding. In the present study, we show that the SSRI paroxetine binds to phosphofructokinase (PFK) protein using CETSA. We found that mouse brain PFK and recombinant human PFK proteins are stabilized by paroxetine incubation. Chronic paroxetine treatment also significantly increased mouse brain PFK thermal stability. Paroxetine significantly elevated in vitro and in vivo PFK activity. Levels of several metabolites in glutamate- and energy metabolism-related pathways are significantly correlated with PFK activity in mouse hippocampus. Our data show that paroxetine can bind to PFK and affect its activity. Implications of these results for the antidepressant mode of action of paroxetine are discussed.


Assuntos
Transtorno Depressivo Maior , Paroxetina , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Metabolismo Energético , Humanos , Paroxetina/farmacologia , Fosfofrutoquinases , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico
5.
Mol Brain ; 13(1): 19, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051001

RESUMO

Synaptic proteins play an important role for the regulation of synaptic plasticity. Numerous studies have identified and revealed individual synaptic protein functions using protein overexpression or deletion. In neuropathic pain nociceptive stimuli conveyed from the periphery repetitively stimulate neurons in the central nerve system, brain and spinal cord. Neuronal activities change the turnover (synthesis and degradation) rate of synaptic proteins. Thus, the analysis of synaptic protein turnover rather than just expression level change is critical for studying the role of synaptic proteins in synaptic plasticity. Here, we analyzed synaptosomal proteome in the anterior cingulate cortex (ACC) to identify protein turnover rate changes caused by peripheral nerve injury. Whereas PKCγ levels were not altered, we found that the protein's turnover rate decreased after peripheral nerve injury. Our results suggest that postsynaptic PKCγ synthesized by neuronal activities in the ACC is translocated to the postsynaptic membrane with an extended half-life.


Assuntos
Giro do Cíngulo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal , Traumatismos dos Nervos Periféricos/metabolismo , Proteína Quinase C/metabolismo , Proteômica , Animais , Hipocampo/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervo Fibular/lesões , Neuropatias Fibulares/metabolismo , Neuropatias Fibulares/fisiopatologia , Transporte Proteico , Proteólise
6.
PLoS Genet ; 15(9): e1008358, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557158

RESUMO

Stressful life events are major environmental risk factors for anxiety disorders, although not all individuals exposed to stress develop clinical anxiety. The molecular mechanisms underlying the influence of environmental effects on anxiety are largely unknown. To identify biological pathways mediating stress-related anxiety and resilience to it, we used the chronic social defeat stress (CSDS) paradigm in male mice of two inbred strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), that differ in their susceptibility to stress. Using a multi-omics approach, we identified differential mRNA, miRNA and protein expression changes in the bed nucleus of the stria terminalis (BNST) and blood cells after chronic stress. Integrative gene set enrichment analysis revealed enrichment of mitochondrial-related genes in the BNST and blood of stressed mice. To translate these results to human anxiety, we investigated blood gene expression changes associated with exposure-induced panic attacks. Remarkably, we found reduced expression of mitochondrial-related genes in D2 stress-susceptible mice and in exposure-induced panic attacks in humans, but increased expression of these genes in B6 stress-susceptible mice. Moreover, stress-susceptible vs. stress-resilient B6 mice displayed more mitochondrial cross-sections in the post-synaptic compartment after CSDS. Our findings demonstrate mitochondrial-related alterations in gene expression as an evolutionarily conserved response in stress-related behaviors and validate the use of cross-species approaches in investigating the biological mechanisms underlying anxiety disorders.


Assuntos
Ansiedade/genética , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Genômica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , MicroRNAs/genética , Mitocôndrias , Proteômica , RNA Mensageiro/genética , Núcleos Septais/metabolismo , Estresse Psicológico/fisiopatologia , Transcriptoma/genética
7.
Adv Exp Med Biol ; 1118: 163-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747422

RESUMO

High comorbidity and complexity have precluded reliable diagnostic assessment and treatment of psychiatric disorders. Impaired molecular interactions may be relevant for underlying mechanisms of psychiatric disorders but by and large remain unknown. With the help of a number of publicly available databases and various technological tools, recent research has filled the paucity of information by generating a novel dataset of psychiatric interactomes. Different technological platforms including yeast two-hybrid screen, co-immunoprecipitation-coupled with mass spectrometry-based proteomics, and transcriptomics have been widely used in combination with cellular and molecular techniques to interrogate the psychiatric interactome. Novel molecular interactions have been identified in association with different psychiatric disorders including autism spectrum disorders, schizophrenia, bipolar disorder, and major depressive disorder. However, more extensive and sophisticated interactome research needs to be conducted to overcome the current limitations such as incomplete interactome databases and a lack of functional information among components. Ultimately, integrated psychiatric interactome databases will contribute to the implementation of biomarkers and therapeutic intervention.


Assuntos
Transtornos Mentais/diagnóstico , Proteômica , Transcriptoma , Humanos
8.
Sci Rep ; 8(1): 179, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29317657

RESUMO

While N-linked glycosylation has been extensively studied in the context of inflammatory and metabolic disorders, its relationship with major depressive disorder (MDD) and antidepressant treatment response has not been investigated. In our exploratory study, we analysed N-glycan profiles in blood plasma samples collected from MDD patients (n = 18) and found gender-dependent correlations with severity of depressive symptoms prior to initiating antidepressant treatment. In addition, several N-glycosylation traits showed gender-dependent associations with clinical antidepressant response. Follow up proteomics analysis in peripheral blood mononuclear cells (PBMCs) collected from MDD patients (n = 20) identified baseline and post-antidepressant treatment pathway differences between responder and non-responder patients. Reactome data analysis further delineated potential biological reaction differences between responder and non-responder patients. Our preliminary results suggest that specific glycosylation traits are associated with depressive symptom severity and antidepressant response and may be of use as biomarkers.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/sangue , Imunoglobulina G/metabolismo , Polissacarídeos/sangue , Processamento de Proteína Pós-Traducional , Adulto , Idoso , Biomarcadores/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Glicosilação , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo
9.
Cell Rep ; 22(3): 748-759, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29346771

RESUMO

Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.


Assuntos
Antígeno CD56/metabolismo , Giro do Cíngulo/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Giro do Cíngulo/patologia , Masculino , Camundongos , Traumatismos dos Nervos Periféricos/patologia , Sinapses/patologia
10.
Sci Rep ; 6: 35317, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731396

RESUMO

Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used drugs for the treatment of psychiatric diseases including major depressive disorder (MDD). For unknown reasons a substantial number of patients do not show any improvement during or after SSRI treatment. We treated DBA/2J mice for 28 days with paroxetine and assessed their behavioral response with the forced swim test (FST). Paroxetine-treated long-time floating (PLF) and paroxetine-treated short-time floating (PSF) groups were stratified as proxies for drug non-responder and responder mice, respectively. Proteomics and metabolomics profiles of PLF and PSF groups were acquired for the hippocampus and plasma to identify molecular pathways and biosignatures that stratify paroxetine-treated mouse sub-groups. The critical role of purine and pyrimidine metabolisms for chronic paroxetine treatment response in the mouse was further corroborated by pathway protein expression differences in both mice and patients that underwent chronic antidepressant treatment. The integrated -omics data indicate purine and pyrimidine metabolism pathway activity differences between PLF and PSF mice. Furthermore, the pathway protein levels in peripheral specimens strongly correlated with the antidepressant treatment response in patients. Our results suggest that chronic SSRI treatment differentially affects purine and pyrimidine metabolisms, which may explain the heterogeneous antidepressant treatment response and represents a potential biosignature.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Paroxetina/farmacologia , Purinas/metabolismo , Pirimidinas/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos DBA , Proteoma/metabolismo , Natação , Fatores de Tempo
11.
Neurobiol Aging ; 35(5): 990-1001, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24268884

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aß) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library. Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aß1-42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aß plaque deposition and Aß levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, ß-, or γ-secretase, but levels of insulin degrading enzyme, an Aß degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Encéfalo/metabolismo , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Placa Amiloide/metabolismo , 1-Metil-4-fenilpiridínio/efeitos adversos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Ácido Glutâmico/efeitos adversos , Humanos , Camundongos , Terapia de Alvo Molecular , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos adversos
12.
Neuropharmacology ; 61(1-2): 276-82, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21530554

RESUMO

Mecamylamine (MEC), which was initially developed as a ganglionic blocker for the treatment of hypertension has been investigated as a potent antagonist for most types of nicotinic acetylcholine receptors (nAChRs). Most studies of MEC have focused on its inhibitory effects for nAChRs; however its biological uses have recently been expanded to the treatment of psychological disorders accompanying anxiety-related symptoms. Although MEC shows obvious anxiolytic action, there is no clear evidence on its function. In this study, we investigated whether MEC affects brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. MEC increased BDNF expression in differentiated SH-SY5Y cells and the cerebral cortex region of rat brains. To determine if the anxiolytic effect of MEC is associated with BDNF upregulation, the elevated plus maze (EPM) task was conducted in a dexamethasone (DEX)-induced anxiety model. MEC reduced DEX-induced anxiety-like behavior, and increased BDNF expression in the cerebral cortex of rats. These results suggest that the anxiolytic effect of MEC in EPM might be associated with BDNF upregulation in the cerebral cortex region of rats. The therapeutic efficacy of MEC for anxiety might be partly dependent on BDNF modulation.


Assuntos
Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Encéfalo/metabolismo , Dexametasona/antagonistas & inibidores , Dexametasona/toxicidade , Mecamilamina/farmacologia , Animais , Ansiolíticos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/prevenção & controle , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
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