Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 105
Filtrar
1.
J Neurosci ; 40(22): 4418-4431, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32269106

RESUMO

Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study, we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of WT but not MMP-9-null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of ex vivo γ oscillations in conventionally housed mice. γ power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. Compared with mice that receive concurrent venlafaxine, corticosterone-treated mice also display reduced ex vivo γ power and impaired working memory. Autopsy-derived PFC samples show elevated MMP-9 levels in antidepressant-treated MDD patients compared with controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.SIGNIFICANCE STATEMENT Reduced excitatory neurotransmission occurs with major depressive disorder, and may be normalized by antidepressant treatment. Underlying molecular mechanisms are, however, not well understood. Herein we investigate a potential role for an extracellular protease, released from neurons and known to play a role in learning and memory, in antidepressant-associated increases in excitatory transmission. Our data suggest that this protease, matrix metalloprotease-9, increases branching of excitatory neurons and concomitantly attenuates the perineuronal net to potentially reduce inhibitory input to these neurons. Matrix metalloprotease-9 may thus enhance overall excitatory/inhibitory balance and neuronal population dynamics, which are important to mood and memory.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ritmo Gama , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Estresse Psicológico/complicações , Cloridrato de Venlafaxina/farmacologia , Adulto , Idoso , Animais , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Transtorno Depressivo Maior/etiologia , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Memória de Curto Prazo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Piramidais/metabolismo , Células Piramidais/patologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico
2.
Psychopharmacology (Berl) ; 237(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473777

RESUMO

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used drugs for the treatment of depression. Studies have shown that chronic treatment with SSRIs and SNRIs produces a protective effect against oxidative stress. Thioredoxin (Trx) is an antioxidant protein that reverses protein cysteine oxidation and facilitates scavenging reactive oxygen species. OBJECTIVES: The current study is to determine whether the SSRI fluoxetine and the SNRI venlafaxine regulate Trx and protect neuronal cells against protein cysteine oxidation. METHODS: HT22 mouse hippocampal cells were incubated with fluoxetine or venlafaxine for 5 days. Protein levels of Trx, Trx reductase (TrxR), and Trx-interacting protein (Txnip) were measured by immunoblotting analysis. Trx and TrxR activities were analyzed by spectrophotometric method. Protein cysteine sulfenylation was measured by dimedone-conjugation assay, while nitrosylation was measured by biotin-switch assay. RESULTS: We found that treatment with fluoxetine or venlafaxine for 5 days increased Trx and TrxR protein levels but produced no effect on Txnip protein levels. These treatments also increased Trx and TrxR activities. Although treatment with fluoxetine or venlafaxine alone had no effect on sulfenylated and nitrosylated protein levels, both drugs inhibited H2O2-increased sulfenylated protein levels and nitric oxide donor nitrosoglutathione-increased nitrosylated protein levels. Stress increases risk of depression. We also found that treatment with fluoxetine or venlafaxine for 5 days inhibited stress hormone corticosterone-increased total sulfenylated and nitrosylated protein levels. CONCLUSIONS: Our findings suggest that chronic treatment with antidepressants may upregulate Trx, subsequently inhibiting protein sulfenylation and nitrosylation, which may contribute to the protective effect of antidepressants against oxidative stress. Our findings also indicate that thioredoxin is a potential therapeutic target for the treatment of depression.


Assuntos
Fluoxetina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo
3.
Environ Sci Pollut Res Int ; 27(2): 1686-1696, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31755053

RESUMO

The effect of venlafaxine, a pharmaceutical commonly found in aquatic environment, was analyzed on non-target organism, Danio rerio (Hamilton, 1822). D. rerio embryos were treated by two different concentrations of venlafaxine: either concentration relevant in aquatic environment (0.3 µg/L) or concentration that was two orders of magnitude higher (30 µg/L) for the evaluation of dose-dependent effect. Time-dependent effect was rated at 24, 96, and 144 h post-fertilization (hpf). For gene expression, genes representing one of the phases of xenobiotic biotransformation (0 to III) were selected. The results of this study showed that the effect of venlafaxine on the zebrafish embryos is the most evident at hatching (96 hpf). At this time, the results showed a downregulation of gene expression in each phase of biotransformation and in both tested concentrations. In contrast, an upregulation of most of the genes was observed 144 hpf for both tested venlafaxine concentrations. The study shows that venlafaxine can affect the gene expression of biotransformation enzymes in D. rerio embryos even in the environmentally relevant concentration and thus disrupt the process of biotransformation. Moreover, the pxr regulation of genes seems to be disrupted after venlafaxine exposure in dose- and time-dependent manner.


Assuntos
Antidepressivos/farmacologia , Embrião não Mamífero/enzimologia , Regulação Enzimológica da Expressão Gênica , Cloridrato de Venlafaxina/farmacologia , Peixe-Zebra , Animais , Biotransformação , Embrião não Mamífero/efeitos dos fármacos , Poluentes Químicos da Água/farmacologia
4.
Psychiatry Res ; 284: 112690, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31757642

RESUMO

OBJECTIVE: We aimed to study the association among venlafaxine antidepressive outcome, NR3C2 gene polymorphisms and the change of two neuroendocrine hormones during treatment. METHODS: 195 Chinese Han major depressive disorder (MDD) patients were recruited and received a 6-week venlafaxine treatment in this study. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) levels were measured at the beginning and at the end of treatment. Six single-nucleotide polymorphisms (SNPs) (NR3C2: rs1512325, rs1512342, rs2070951; NR3C1: rs6191, rs6196, rs10482614) were selected for high-throughput SNP genotyping. Allele and genotype frequencies of them were compared between remission and non-remission groups. RESULTS: We found that genotype frequency of the rs1512325 located in the NR3C2 gene was significantly different between remission and non-remission groups respectively (p < 0.05). Meanwhile, the frequency of the rs1512325 C-allele was significantly lower (p < 0.05) in remission group. The TSH concentration significantly increased after venlafaxine treatment in remission group (p < 0.05). CONCLUSION: The rs1512325 in NR3C2 gene and TSH concentration may be related to venlafaxine treatment outcome in Chinese Han MDD patients.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Receptores de Mineralocorticoides/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Transtorno Depressivo Maior/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores de Mineralocorticoides/genética , Tireotropina/sangue , Resultado do Tratamento
5.
Pharmacol Biochem Behav ; 187: 172817, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655085

RESUMO

INTRODUCTION: Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. AIM: To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior. METHODS: Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. RESULTS: Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. CONCLUSIONS: Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Mirtazapina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Quimioterapia Combinada/efeitos adversos , Feminino , Locomoção/efeitos dos fármacos , Masculino , Mirtazapina/administração & dosagem , Mirtazapina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Natação , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêutico
6.
J Steroid Biochem Mol Biol ; 195: 105470, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509772

RESUMO

Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.


Assuntos
Aromatase/metabolismo , Placenta/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Serotonina/farmacologia , Células Cultivadas , Citalopram/farmacologia , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Humanos , Simulação de Acoplamento Molecular , Paroxetina/farmacologia , Placenta/metabolismo , Gravidez , Sertralina/farmacologia , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Cloridrato de Venlafaxina/farmacologia
7.
Behav Pharmacol ; 30(8): 722-729, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31503069

RESUMO

Piperlongumine, an alkaloid compound extracted from Peper longum L, has been reported to produce neuroprotective effects in the brain and exert various pharmacological activities such as antitumor, antiangiogenic, anti-inflammatory and analgesic properties. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of piperlongumine in a chronic unpredictable stress (CUS) model. We found that, with venlafaxine as a positive control, orally administered piperlongumine (12.5 and 25 mg/kg) for 7 days, not a single dose, significantly reduced immobility time in the forced swimming test, but did not alter locomotor activity in the open field test, indicating that piperlongumine has antidepressant-like effects without nonspecific motor changes. Then, using the CUS model of depression, piperlongumine was administrated orally for 4 weeks, followed by sucrose preference and forced swimming tests to evaluate the depressive-like behaviors. We found that piperlongumine reversed both the decreased sucrose preference and increased immobility time in rats exposed to CUS. In addition, piperlongumine also reversed the increase in proinflammatory cytokine levels in the hippocampus of rats in the CUS model. Altogether, the present study demonstrated that piperlongumine exhibits the antidepressant-like effects in rats, which may be mediated by the inhibition of the neuronal inflammation in the hippocampus.


Assuntos
Depressão/tratamento farmacológico , Dioxolanos/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Cloridrato de Venlafaxina/farmacologia
8.
Brain Res Bull ; 153: 171-180, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31445056

RESUMO

Although thought as a serotonin and norepinephrine reuptake inhibitor (SNRI), the antidepressant mechanisms of venlafaxine remain unknown. Previous reports have shown the role of peroxisome proliferator activated receptor α (PPARα) in depression. In this study, we investigated whether the antidepressant-like effects of venlafaxine require PPARα. We first examined whether repeated venlafaxine administration reversed the effects of chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) on PPARα in the hippocampus and medial prefrontal cortex (mPFC). Then, the pharmacologcial inhibitors of PPARα, GW6471 and MK886, were used to assay if the protecting effects of venlafaxine against chronic stress were prevented by PPARα blockade. Furthermore, gene knockdown of PPARα by AAV-PPARα-shRNA was also used. It was found that venlafaxine treatment fully restored the decreasing effects of CUMS and CRS on the hippocampal PPARα expression. Pharmacological inhibition of PPARα significantly attenuated the antidepressant-like effects of venlafaxine in mice. Moreover, gene knockdown of hippocampal PPARα also fully abolished the antidepressant-like actions of venlafaxine in mice. Collectively, hippocampal PPARα is an antidepressant target of venlafaxine.


Assuntos
Depressão/tratamento farmacológico , PPAR alfa/metabolismo , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Encéfalo/metabolismo , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/efeitos dos fármacos , PPAR alfa/genética , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Lobo Temporal/metabolismo , Cloridrato de Venlafaxina/metabolismo
9.
Braz J Cardiovasc Surg ; 34(3): 290-296, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310467

RESUMO

OBJECTIVE: In this study, we aimed to examine the effects of amitriptyline, fluoxetine, tranylcypromine and venlafaxine on saphenous vein grafts in coronary artery bypass graft surgeries. METHODS: 59 patients (40 males and 19 females; mean age 65.1 years, distribution: 45-84 years) who had coronary artery bypass graft surgery between February 2014 and May 2016 were included in the study. After the saphenous vein grafts with intact and denuded endothelium were precontracted with 3×10-6M phenylephrine, amitriptyline, fluoxetine and tranylcypromine were cumulatively added to isolated organ baths in the range of 10-11-3x10-5M, while venlafaxine was added in the range of 10-9-3×10-5M. Then, the antidepressant-induced relaxation responses were recorded isometrically. RESULTS: While the relaxation response of amitriptyline at -6.42 (Log M) was 74.6%, the response at -6.32 (Log M) was 75.5%. While the relaxation response at -6.46 (Log M) of fluoxetine was 68.02%, the response at -6.02 (Log M) was 72.12%. While the relaxation response of tranylcypromine at -7.53 (Log M) was 61.13%, the response at -7.23 (Log M) was 65.53%. While the relaxation response of venlafaxine at -6.21 (Log M) was 29.98%, the response at -5.90 (Log M) was 32.96%. CONCLUSION: The maximum relaxation at minimum and maximum therapeutic concentrations was obtained with amitriptyline, fluoxetine and tranylcypromine, and the minimum relaxation was obtained with venlafaxine. The relaxation responses were independent of the endothelium.


Assuntos
Amitriptilina/farmacologia , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Veia Safena/efeitos dos fármacos , Veia Safena/transplante , Tranilcipromina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Ponte de Artéria Coronária/métodos , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Valores de Referência , Transplantes/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
10.
Endocrinology ; 160(9): 2137-2142, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31305910

RESUMO

Owing to the prevalence of depression during childbearing, mothers can be prescribed multiple antidepressants; however, little is known about the risk and consequences to the offspring or subsequent generations. Fluoxetine (FLX) is usually the first-line of pharmacological treatment for affective disorders in pregnant women, with venlafaxine (VEN) used as secondary treatment. Given that FLX and VEN readily cross the placenta, a fetus from a treated pregnant woman is potentially at risk of the endocrine disruptive effects of these chemicals. Pharmaceutical agents, including FLX and VEN, reach aquatic ecosystems through sewage release; thus, fish could also be inadvertently affected. We report the results from a 6-day FLX exposure during early zebrafish development to an environmentally relevant level (0.54 µg/L in water) and a concentration detected in the cord blood of FLX-treated pregnant women (54 µg/L in water). The FLX exposure reduced the stress response (arithmetic difference between the stress-induced and unstressed whole-body cortisol levels) in the adult female and male zebrafish, an effect that persisted for four generations. To model the possibility of a second antidepressant exposure, filial generation 4 was exposed to VEN (5 µg/L). We found that FLX exposure sensitized these descendants to VEN. VEN treatment further suppressed cortisol production in females and decreased spawning rates in adult pairs. This is an important demonstration that in an animal model, a brief ancestral exposure of great-great-grandparents to the selective serotonin reuptake inhibitor FLX will shape the physiological responses of future generations to the serotonin and norepinephrine reuptake inhibitor VEN.


Assuntos
Fluoxetina/farmacologia , Hidrocortisona/biossíntese , Inibidores de Captação de Serotonina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Peixe-Zebra/fisiologia , Animais , Feminino , Masculino , Exposição Materna/efeitos adversos
11.
Mol Med Rep ; 20(3): 2954-2962, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322231

RESUMO

A number of studies have linked abnormalities in the function of the serotonergic and noradrenergic systems to the pathophysiology of depression. It has been reported that selective serotonin reuptake inhibitors promote the expression of tryptophan hydroxylase (TPH), which is involved in the synthesis of serotonin. However, limited evidence of TPH alteration has been found in selective serotonin and noradrenaline reuptake inhibitors (SNRIs), and more key enzymes need to be investigated. The aim of the present study was to determine whether venlafaxine (VLX; a classical SNRI) regulates TPH and other key enzymes responsible for the synthesis and metabolism of monoaminergic transmitters in rats with chronic unpredictable stress (CUS). The present results suggested that CUS­exposed rats exhibited decreased locomotor activity in the open­field test and increased immobility time in the forced swim test, as compared with the controls. Pretreatment with VLX (20 mg/kg) significantly increased locomotor activity and reduced immobility time in the CUS­exposed rats. In addition, VLX (20 mg/kg) treatment prevented the CUS­induced reduction in tyrosine hydroxylase and TPH expression in the cortex and hippocampus. Furthermore, VLX alleviated the CUS­induced oxidative stress in the serum, cortex and hippocampus. However, VLX administration did not have an effect on indoleamine­2,3­dioxygenase overexpression in the hippocampus. It was therefore concluded that the regulation of abnormalities in the synthesis and metabolism of monoaminergic transmitters may be associated with the antidepressant effects of VLX, suggesting that multimodal pharmacological treatments can efficiently treat depression.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Monoaminas Biogênicas/metabolismo , Depressão/tratamento farmacológico , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Cloridrato de Venlafaxina/uso terapêutico , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Monoaminoxidase/metabolismo , Ratos Sprague-Dawley , Estresse Fisiológico/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia
12.
Gynecol Endocrinol ; 35(12): 1054-1058, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31192745

RESUMO

Estrogen deficiency increases the incidence of female anxiety disorders; however, whether estrogen deficiency alters responses to anxiolytic drugs is unknown. We studied whether long-term estrogen deprivation (ovariectomy, OVX) changes the behavior of mice to anxiolytic drugs (buspirone, diazepam, and venlafaxine), using the elevated plus maze (EPM) test. The percentages of EPM open-arm time and EPM open-arm entries of the OVX mice decreased significantly compared to control, and sham mice 2 months after OVX. The response to buspirone increased in the OVX mice at 1 week, while OVX decreased the response to diazepam at 2 months. Moreover, we found the efficacy of diazepam was significantly decreased, compared to buspirone and venlafaxine, at 2 months. These results suggest that OVX may change responses to different anxiolytic drugs. Not all anti-anxiety drugs appear to be suitable for anxiety caused by estrogen deficiency.


Assuntos
Ansiolíticos/farmacologia , Ansiedade , Comportamento Animal/efeitos dos fármacos , Estrogênios/deficiência , Ovariectomia , Animais , Buspirona/farmacologia , Diazepam/farmacologia , Camundongos , Cloridrato de Venlafaxina/farmacologia
13.
Pharmacol Rep ; 71(4): 573-582, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170658

RESUMO

BACKGROUND: Macrophages, involved in the pathogenesis of pain, express a variety of receptors enabling responsiveness to certain medications, including adjuvant analgesics (AAs), that are effective in neuropathic pain and include drugs not primarily indicated for pain treatment, such as anticonvulsants or antidepressants. Their analgesic effects are likely associated with immunomodulatory activity, that remain undefined. Thus, current research aimed at examining the impact of AAs on morphine-induced effects exerted on mouse immunity. METHODS: Macrophages from mice treated with morphine with or without gabapentin, amitriptyline or venlafaxine, were either subjected to phagocytosis assay, cultured to evaluate the generation of cytokines, or were pulsed with either corpuscular antigen or hapten and transferred to naive recipients to induce humoral or cellular response, respectively. Active contact hypersensitivity was also elicited in drug-treated mice. RESULTS: We observed that repeatedly administered morphine and AAs reduced antigen phagocytosis by macrophages. Further, amitriptyline with morphine enhanced basal secretion of cytokines by macrophages, and all drugs tended to decrease LPS-stimulated release of pro-inflammatory cytokines. Morphine and AAs impacted the expression of phagocytosis and antigen-presentation markers on macrophages, which led to the reduced ability of morphine-affected macrophages to induce B-cell secretion of specific antibodies, and the addition of AAs strengthened this effect. Finally, gabapentin and venlafaxine suppressed the contact hypersensitivity reaction, while amitriptyline seemed to have the opposite effect. CONCLUSIONS: Our study demonstrated a significant anti-inflammatory activity of AAs across a broad spectrum of macrophage immune functions, which is likely critical to their analgesic activity supporting the beneficial effect of morphine.


Assuntos
Adjuvantes Farmacêuticos/farmacologia , Analgésicos Opioides/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Morfina/farmacologia , Fagocitose/efeitos dos fármacos , Adjuvantes Farmacêuticos/administração & dosagem , Amitriptilina/administração & dosagem , Amitriptilina/farmacologia , Analgésicos Opioides/administração & dosagem , Animais , Apresentação do Antígeno/efeitos dos fármacos , Citocinas/metabolismo , Gabapentina/administração & dosagem , Gabapentina/farmacologia , Imunidade Humoral/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos CBA , Morfina/administração & dosagem , Fagocitose/imunologia , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacologia
14.
Life Sci ; 226: 68-76, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928406

RESUMO

AIMS: Rheumatoid arthritis is usually accompanied by various comorbidities especially on the psychological side such as depression. This study aimed at revealing the potential curative effects of venlafaxine (VFX), a serotonin/norepinephrine reuptake inhibitor (SNRI), on experimentally-induced arthritis in rats. METHODS: Arthritis was induced by injecting complete Freund's adjuvant (CFA, 0.1 ml, s.c.). One day thereafter, VFX (50 mg/kg, p.o.) was given for 21 days. Methotrexate was used as a standard disease modifying anti-rheumatic drug. KEY FINDINGS: CFA injection caused prominent arthritis evident by the increase in the hind paw and ankle diameter accompanied by elevating tumor necrosis factor-alpha, interleukin-6, interleukin-17 and matrix metalloproteinase-3 levels, effects that were diminished by VFX. Moreover, VFX down regulated gene expressions of receptor activator of nuclear factor kappa-B (NF-кB) ligand and signal transducer and activator of transcription-3 beside hampering immunohistochemical expression of vascular endothelial growth factor and NF-кB. This SNRI also improved the oxidant status of the hind limb as compared to the arthritic group. Nonetheless, MTX was better in amendment of arthritis authenticated by its effect on some inflammatory and oxidative stress biomarkers. SIGNIFICANCE: This study provides a novel therapeutic use of VFX as a considerable anti-arthritic drug and offers an incentive to expand its use in RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Cloridrato de Venlafaxina/metabolismo , Cloridrato de Venlafaxina/farmacologia , Animais , Antirreumáticos , Artrite Experimental/metabolismo , Artrite Reumatoide , Biomarcadores , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Interleucina-17/metabolismo , Interleucina-6 , Masculino , Metaloproteinase 3 da Matriz , Metotrexato/farmacologia , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo , Ligante RANK/efeitos dos fármacos , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa
15.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987090

RESUMO

The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α2-adrenergic antagonist idazoxan (10 µg, i.t.), but not the α1-adrenergic antagonist prazosin (10 µg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 µg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 µg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α2-adrenergic receptor, and both α2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Cloridrato de Venlafaxina/uso terapêutico , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos alfa/uso terapêutico , Analgésicos/farmacologia , Animais , Temperatura Baixa , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/complicações , Norepinefrina/metabolismo , Oxaliplatina/administração & dosagem , Receptores Adrenérgicos alfa/metabolismo , Serotonina/metabolismo , Fatores de Tempo , Cloridrato de Venlafaxina/farmacologia
16.
Saudi Med J ; 40(4): 339-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30957126

RESUMO

OBJECTIVES: To investigate the effects of venlafaxine (VEN) on the relapse of methamphetamine (METH)-induced conditioned place preference (CPP) in rats. METHODS: This study was conducted at the Department of Pharmacology and Toxicology, and the Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia between May  2017 and October 2018. A total of 32 male Wistar rats were used in this study. Rats were divided to receive either METH or saline during the conditioning phase. Following the acquisition of METH-induced CPP, the animals were randomly divided to receive saline or VEN for 21 days instead of METH during the extinction training. The reinstatement was initiated by re-exposure to a single dose of METH to test any anti-reinstatement effects of VEN. Results: Two-way repeated measures Analysis of Variance (ANOVA) (time × chamber) was used to analyze time spent in conditioning chambers, while distance traveled was analyzed using one-way ANOVA. Saline or VEN, when administered alone, did not affect CPP or locomotor activity results. A priming intraperitoneal injection of METH reinstated CPP in the animals treated with saline during the extinction phase. Interestingly, VEN treatment blocked METH-induced CPP. CONCLUSION: Venlafaxine effects on the reinstatement of METH-induced CPP are not likely due to nonspecific effects on locomotor activity. This beneficial effect of VEN on relapse to METH-induced CPP could be due to its antidepressant effects. Venlafaxine can thus be a potential therapeutic option in the treatment of relapse to METH-seeking behaviors.


Assuntos
Antidepressivos de Segunda Geração , Comportamento Aditivo/tratamento farmacológico , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacologia , Animais , Condicionamento Clássico , Infusões Parenterais , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Recidiva
17.
J Psychopharmacol ; 33(6): 748-756, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30789286

RESUMO

AIMS: The Wistar-Kyoto rat has been validated as an animal model of treatment-resistant depression. Here we investigated a role of dopamine D2 and D3 receptors in the ventro-medial prefrontal cortex in the mechanism of action of deep brain stimulation in Wistar-Kyoto rats and venlafaxine in Wistar rats. METHODS: Wistar or Wistar-Kyoto rats were exposed chronically to chronic mild stress. Wistar rats were treated chronically with venlafaxine (10 mg/kg) beginning after two weeks of chronic mild stress; Wistar-Kyoto rats received two sessions of deep brain stimulation before behavioural tests. L-742,626 (1 µg), a D2 receptor agonist, or 7-OH DPAT (3 µg), a D3 receptor antagonist, were infused into the ventro-medial prefrontal cortex immediately following the exposure trial in the Novel Object Recognition Test, and discrimination between novel and familiar object was tested one hour later. RESULTS: Chronic mild stress decreased sucrose intake and impaired memory consolidation; these effects were reversed by venlafaxine in Wistar rats and deep brain stimulation in Wistar-Kyoto rats. In control animals, L-742,626 and 7-OH DPAT also impaired memory consolidation. In Wistar rats, venlafaxine reversed the effect of L-742,626 in controls, but not in the chronic mild stress group, and venlafaxine did not reverse the effect of 7-OH DPAT in either group. In Wistar-Kyoto rats, deep brain stimulation reversed the effect of both L-742,626 and 7-OH DPAT in both control and chronic mild stress groups. CONCLUSIONS: We conclude that the action of venlafaxine to reverse the impairment of memory consolidation caused by chronic mild stress in Wistar rats involves D2 receptors in the ventro-medial prefrontal cortex; but the effect of deep brain stimulation to reverse the same effect in Wistar-Kyoto rats does not.


Assuntos
Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Cloridrato de Venlafaxina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Estimulação Encefálica Profunda/métodos , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo Resistente a Tratamento/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Modelos Animais , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Receptores de Dopamina D3 , Tetra-Hidronaftalenos/farmacologia
18.
Neuroreport ; 30(4): 255-261, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30640193

RESUMO

Venlafaxine (VEN) is a widely used antidepressant as a serotonin-reuptake and norepinephrine-reuptake inhibitor. It is used primarily in depression, especially with generalized anxiety disorder or chronic pain. This medicine is of interest because its mechanisms involved multiple aspects. In the current study, the antidepressant action of VEN was investigated by studying the histone acetylation and expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) in rats exposed to chronic unpredicted stress (CUS) for 28 days. Male Sprague-Dawley rats were divided into a control group, VEN-treated control group, CUS group, and VEN-treated CUS group. VEN (23.4 mg/kg once daily) was administered to rats by intragastric gavage, whereas the same volume of vehicle was given to rats in the control and model groups. Rat behaviors, acetylated H3 at lysine 9 (acH3K9), acetylated H3 at lysine 14 (acH3K14), acetylated H4 at lysine 12 (acH4K12), histone deacetylase 5, and TH and TPH expression in the hippocampus were determined. Chronic VEN treatment significantly relieved the anxiety- and depression-like behaviors, prevented the increase of histone deacetylase 5 expression and decrease of acH3K9 level, and promoted TH and TPH protein expression in the hippocampus of CUS rats. The results suggest that the preventive antidepressant mechanism of VEN is partly involved in the blocking effects on histone de-acetylated modification and then increasing TH, TPH expression.


Assuntos
Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Triptofano Hidroxilase/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Acetilação/efeitos dos fármacos , Animais , Depressão/metabolismo , Hipocampo/metabolismo , Histonas/efeitos dos fármacos , Histonas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
19.
J Neurochem ; 148(6): 810-821, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30697747

RESUMO

Drugs that target monoaminergic transmission represent a first-line treatment for major depression. Though a full understanding of the mechanisms that underlie antidepressant efficacy is lacking, evidence supports a role for enhanced excitatory transmission. This can occur through two non-mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms such as enhanced dendritic arborization. Another mechanism involves reduced inhibitory function, which occurs with the rapid antidepressant ketamine. Consistent with this, GABAergic interneuron-mediated cortical inhibition is linked to reduced gamma oscillatory power, a rhythm also diminished in depression. Remission of depressive symptoms correlates with restoration of gamma power. As a result of strong excitatory input, reliable GABA release, and fast firing, PV-expressing neurons (PV neurons) represent critical pacemakers for synchronous oscillations. PV neurons also represent the predominant GABAergic population enveloped by perineuronal nets (PNNs), lattice-like structures that localize glutamatergic input. Disruption of PNNs reduces PV excitability and enhances gamma activity. Studies suggest that monoamine reuptake inhibitors reduce integrity of the PNN. Mechanisms by which these inhibitors reduce PNN integrity, however, remain largely unexplored. A better understanding of these issues might encourage development of therapeutics that best up-regulate PNN-modulating proteases. We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine increases hippocampal matrix metalloproteinase (MMP)-9 levels as determined by ELISA and concomitantly reduces PNN integrity in murine hippocampus as determined by analysis of sections following their staining with a fluorescent PNN-binding lectin. Moreover, venlafaxine-treated mice (30 mg/kg/day) show an increase in carbachol-induced gamma power in ex vivo hippocampal slices as determined by local field potential recording and Matlab analyses. Studies with mice deficient in matrix metalloproteinase 9 (MMP-9), a protease linked to PNN disruption in other settings, suggest that MMP-9 contributes to venlafaxine-enhanced gamma power. In conclusion, our results support the possibility that MMP-9 activity contributes to antidepressant efficacy through effects on the PNN that may in turn enhance neuronal population dynamics involved in mood and/or memory. Cover Image for this issue: doi: 10.1111/jnc.14498.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Ritmo Gama/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Rede Nervosa/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Feminino , Ritmo Gama/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteólise/efeitos dos fármacos
20.
Int J Neuropsychopharmacol ; 22(4): 278-285, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649319

RESUMO

BACKGROUND: The in vivo binding of clinical dose of venlafaxine on norepinephrine transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin transporter than that to norepinephrine transporter. Although serotonin transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of norepinephrine transporter occupancy in the human brain. METHODS: This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of norepinephrine transporter were also estimated. RESULTS: The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P = .0004 < .05/2). The norepinephrine transporter occupancy (8-61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. CONCLUSIONS: This study demonstrates that clinically relevant doses of venlafaxine extended-release block the norepinephrine transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin transporter and norepinephrine transporter blockades.


Assuntos
Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas , Tomografia por Emissão de Pósitrons , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Cloridrato de Venlafaxina/administração & dosagem , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...