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1.
Life Sci ; 245: 117307, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954746

RESUMO

AIM: To investigate whether a chronic 5-HT reuptake inhibitor (i.e. Fluoxetine-FLX) exposure in young adult rats overfed during suckling period would modulate interscapular brown adipose tissue (iBAT) mitochondria and browning agents in white adipose tissue (WAT). METHODS: Male Wistar rats were assigned into either a normofed group (n = 9 per group) or an overfed group (n = 3 per group) induced by litter size reduction at postnatal day 3 (PND3). Pharmacological manipulation was carried out between PND39 and PND59 and groups were assigned accordingly: Normofed + vehicle solution - NaCl 0.9% (NV group), normofed + FLX solution - 10 mg/kg b.w. (NF group), overfed + vehicle (OV group) and overfed + FLX (OF group). We evaluated mitochondrial oxygen consumption and reactive species (RS) production, oxidative stress analyses (MDA concentration, carbonyl content, REDOX state [GSH/GSSG], global oxy score) in the iBAT, gene (leptin, Ucp1, Sirt1, Pgc1α and Prdm16) and protein (UCP1) expression in the iBAT and epididymal WAT (eWAT). KEY FINDINGS: OV group increased body weight gain, Lee index and oxidative stress in the iBAT. Both FLX-treated groups showed less weight gain compared to their controls. OF group showed different leptin expression in the WAT and iBAT; increased functional UCP1 content and mitochondrial activity with less oxidative stress in the iBAT and upregulation of browning genes in eWAT (Pgc1α, Prdm16 and Ucp1). CONCLUSION: Altogether our findings indicated that FLX treatment in young adult overfed animals improved the iBAT mitochondrial function, reduced oxidative stress and induced transcriptional activation of browning agents in white adipose tissue.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fluoxetina/farmacologia , Mitocôndrias/efeitos dos fármacos , Hipernutrição/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína Desacopladora 1/metabolismo
2.
Anticancer Res ; 39(11): 6155-6163, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704843

RESUMO

BACKGROUND/AIM: Fluoxetine, an antidepressant, has cytotoxic effects on several cancer cell lines, while paclitaxel is an antineoplastic agent for various cancers. The aim of this study was to evaluate whether fluoxetine enhances the cytotoxic effect of paclitaxel in gastric adenocarcinoma cells and determine the mechanism of cell death. MATERIALS AND METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to examine cell viability and perform cell cycle analysis. Annexin V propidium iodide (PI) staining, 4',6-diamidino-2-phenylindole (DAPI) staining, caspase-3/7 assay, and western blot analysis were performed for determining cell death. RESULTS: Fluoxetine enhanced the anti-proliferative effect of paclitaxel. Fluoxetine-paclitaxel combination caused G2/M arrest and increased events in the sub G0/G1 phase in a time and dose-dependent manner, indicating apoptotic cell death. Combination treatment caused an increase in early apoptotic and late apoptotic cell death compared to single treatment alone. CONCLUSION: Fluoxetine enhanced the antiproliferation effect of paclitaxel in gastric adenocarcinoma AGS cells and the combination caused cell death by triggering apoptosis and necroptosis.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Fluoxetina/farmacologia , Necrose , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Captação de Serotonina/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas
3.
Life Sci ; 239: 116869, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678277

RESUMO

AIM: The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. MAIN METHODS: Male Wistar rats were exposed to either LPS (50 µg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional groups of rats were exposed to LPS/CMS protocol and treated with either pentoxifylline (PTX), fluoxetine (FLX) or a combination of both. Rats were examined for behavioral, neurochemical, gene expression and mitochondrial ultra-structural changes. KEY FINDINGS: LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. SIGNIFICANCE: Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK.


Assuntos
Fluoxetina/farmacologia , Mitocôndrias/efeitos dos fármacos , Pentoxifilina/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , DNA Mitocondrial/metabolismo , Metabolismo Energético , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Biogênese de Organelas , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
4.
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
5.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480244

RESUMO

Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.


Assuntos
Fluoxetina/farmacologia , Ácido Glutâmico/metabolismo , Proteínas SNARE/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Canais de Cálcio/metabolismo , Exocitose/efeitos dos fármacos , Feminino , Humanos , Modelos Neurológicos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/fisiologia , Proteína Quinase C/metabolismo , Ratos Wistar
6.
Int J Mol Sci ; 20(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480539

RESUMO

An olfactory bulbectomy (OBX) rodent is a widely-used model for depression (especially for agitated depression). The present study aims to investigate the hippocampus metabolic profile and autophagy-related pathways in OBX rats and to explore the modulatory roles of fluoxetine. OBX rats were given a 30-day fluoxetine treatment after post-surgery rehabilitation, and then behavioral changes were evaluated. Subsequently, the hippocampus was harvested for metabonomics analysis and Western blot detection. As a result, OBX rats exhibited a significantly increased hyperemotionality score and declined spatial memory ability. Fluoxetine reduced the hyperemotional response, but failed to restore the memory deficit in OBX rats. Sixteen metabolites were identified as potential biomarkers for the OBX model including six that were rectified by fluoxetine. Disturbed pathways were involved in amino acid metabolism, fatty acid metabolism, purine metabolism, and energy metabolism. In addition, autophagy was markedly inhibited in the hippocampus of OBX rats. Fluoxetine could promote autophagy by up-regulating the expression of LC3 II, beclin1, and p-AMPK/AMPK, and down-regulating the levels of p62, p-Akt/Akt, p-mTOR/mTOR, and p-ULK1/ULK1. Our findings indicated that OBX caused marked abnormalities in hippocampus metabolites and autophagy, and fluoxetine could partly redress the metabolic disturbance and enhance autophagy to reverse the depressive-like behavior, but not the memory deficits in OBX rats.


Assuntos
Autofagia , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo/metabolismo , Transtornos da Memória , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Redes e Vias Metabólicas , Bulbo Olfatório/cirurgia , Ratos , Ratos Sprague-Dawley
7.
Life Sci ; 234: 116751, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415771

RESUMO

AIMS: The present study aims to investigate the impacts of olfactory bulbectomy (OBX) on urinary metabolic profile and tryptophan metabolites in prefrontal cortex (PFC) of rats, and to explore the regulation effects of fluoxetine. MAIN METHODS: OBX model was developed by aspiration of olfactory bulbs. After fluoxetine treatment (10 mg/kg) for 14 days, urine samples were collected and behavior tests were applied. Tryptophan (TRP) metabolites and neurotransmitters in PFC were determined by prominence ultrafast liquid chromatography-QTRAP-mass spectrometry, and tryptophan hydroxylase 2 (TPH2) and indoleamine-2,3-dioxygenase 1 (IDO1) were evaluated by western blot. Urinary metabolites were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry-based metabonomics strategy. KEY FINDING: OBX rats showed hyperlocomotion in open field, hyperactivity in open arm and despair status, and fluoxetine reserved these behavioral abnormalities. The levels of TRP, 5-HIAA, 5-HIAA/5-HT ratio and DA increased, while kynurenine and 5-HT decreased in PFC of OBX rats. The activities of TPH2 and IDO1were inhibited after OBX. Twenty-six altered metabolites were identified as potential biomarkers in OBX rats involved in tryptophan metabolism, gut microbiota metabolism, energy metabolism, purine metabolism, ascorbate and aldarate metabolism, and tyrosine metabolism. Among them, 15 abnormal metabolites were corrected by fluoxetine to some extent. SIGNIFICANCE: Our results revealed that urinary metabolic profile changed greatly in OBX rats, and identified biomarkers might be helpful for the diagnosis of agitated depression. The regulation effects of fluoxetine on urinary metabolic profile and tryptophan metabolites in PFC might contribute to its antidepressant action in OBX rats.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Fluoxetina/uso terapêutico , Metaboloma/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/urina , Modelos Animais de Doenças , Fluoxetina/farmacologia , Masculino , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Sprague-Dawley , Triptofano/metabolismo
8.
Nat Commun ; 10(1): 3768, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434877

RESUMO

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.


Assuntos
Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
9.
Zebrafish ; 16(5): 443-450, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31436486

RESUMO

The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Fluoxetina/farmacologia , Imipramina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos Tricíclicos/administração & dosagem , Feminino , Fluoxetina/administração & dosagem , Imipramina/administração & dosagem , Masculino , Aprendizagem em Labirinto , Inibidores de Captação de Serotonina/administração & dosagem , Peixe-Zebra/fisiologia
10.
Life Sci ; 232: 116508, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278948

RESUMO

AIM: Fluoxetine, one of the first newer SSRI antidepressant, is an extremely popular treatment for depression that could improve mental health problems. Many recent studies have suggested that SSRI have potential beneficial effects on skeletal muscle tissue. MAIN METHOD: We evaluated the potential beneficial effects of oral fluoxetine (18 mg/kg/day for 6 weeks) on muscle performance, after 6 weeks of physical exercise on treadmill. Male mice were randomly assigned to four groups (n = 12 per group) for treatment. Each group received treatment with following specifications: 1) no exercise with vehicle treatment (SED-S); 2) no exercise with fluoxetine treatment (SED-F); 3) exercise with vehicle treatment (EX-S); and 4) exercise with fluoxetine treatment (EX-F). Exercise performances were assessed based on the exhaustive running time and forelimb grip strength, anxious behavior by elevated plus-maze and open-field tests. Mitochondrial enzymes activity and ROS production were measured in the gastrocnemius and soleus muscles. KEY FINDING: Fluoxetine treatment had a significant effect on maximal aerobic capacity in mice without exercise, but more significant effects on gripping strength and anxiety when combined with exercise training, e.g. increased strength and decreased anxiety. SIGNIFICANCE: Fluoxetine treatment and exercise stimulation also had synergistic effects on strength and increased mitochondrial activity, cellular oxidative and antioxidant capacity in two different muscles.


Assuntos
Fluoxetina/farmacologia , Esforço Físico/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Oxirredução , Estresse Oxidativo , Condicionamento Físico Animal/fisiologia , Resistência Física/efeitos dos fármacos
11.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1193-1199, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303590

RESUMO

Cognitive behavior is associated with physiological processes that affect the working performance of an individual. Cognitive control is used to override self-serving impulses and behave in socially desirable manner. The objective of the study is to compare the effects of Choline with Fluoxetine and Clozapine for the modulation of cognitive behavior including learning, memory, locomotor, exploratory behavior and anxiety. The study was based on twenty four albino rats divided into four equal groups: (1) Control kept on normal saline (2) Fluoxetine (3) Clozapine (4) Choline. Morris Water Maze (WM) test was used for the psychological assessment based on neural mechanism involved in spatial learning and memory. Open field activity test evaluated locomotor and exploratory behavior. The behavior modulation in WM test and open field activity test was determined at 1st, 3rd, 5th and 7th week. Fluoxetine, Clozapine and Choline were used as drugs and administered to the rat groups mentioned earlier. The modulation of behavior in WM test and Open field activity test was recorded at 1st, 3rd, 5th and 7th week after administering the drugs. Impairment in learning behavior in Fluoxetine treated group was observed at 1st, 3rd, 5th and 7th week and in Clozapine group at 1st and 2nd week when compared to Control (Saline) group. Rise in latency time was observed in Fluoxetine treated group but was not significant. Clozapine and Choline had exhibited beneficial effects in memory retention and prevention of learning impairment. The findings have led to the conclusion that Choline and Clozapine improve the memory retention after continuous administration of 5 and 7 weeks. Moreover, Clozapine has different receptor specificity as compared to Choline. However, both improve the learning capability and enhance the memory in rats. Meanwhile, Fluoxetine did not show any considerable enhancement of memory.


Assuntos
Colina/farmacologia , Clozapina/farmacologia , Cognição/efeitos dos fármacos , Fluoxetina/farmacologia , Animais , Antipsicóticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos
12.
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
13.
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
14.
Eur J Pharmacol ; 857: 172441, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181210

RESUMO

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine. In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/patologia , Fluoxetina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilserinas/metabolismo
15.
PLoS One ; 14(6): e0217519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163038

RESUMO

Fluoxetine (FLX), a widely used antidepressant primarily acting as a selective serotonin reuptake inhibitor (SSRI), has been shown to exhibit other mechanisms of action in various cell types. Consequently, it might have unexpected adverse effects not related to its intended use, possibly in the endocrine regulation of reproduction. We show in the present report that after a 1-hour preincubation of MLTC-1 Leydig cells with FLX, the intracellular cyclic adenosine monophosphate (cAMP) responses to Luteinizing Hormone (LH) and forskolin (FSK) are reduced through AMPK-dependent and -independent pathways respectively. FLX at low concentrations (12.5µM and 25µM) induced this inhibition without triggering AMPK phosphorylation, while higher FLX concentrations (50µM and 100µM) induced AMPK phosphorylation and lowered ATP concentration similarly to Metformin. Pretreatment with the specific AMPK inhibitor Compound C (CpdC), significantly diminished the inhibition of cAMP synthesis caused by high concentration of FLX. Moreover, as expected FLX also caused a decline of steroidogenesis which is under the control of cAMP. Taken together, these findings demonstrate that the inhibition of cAMP synthesis by FLX is dose-dependent and occurs in MLTC-1 cells through two mechanisms, AMPK-independent and AMPK-dependent, at low and high concentrations, respectively. FLX also inhibited hormone-induced steroidogenesis in MLTC-1 cells and mouse testicular Leydig cells, suggesting similar mechanisms in both cell types.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , AMP Cíclico/biossíntese , Fluoxetina/farmacologia , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/farmacologia , Animais , Linhagem Celular , Colforsina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Células Intersticiais do Testículo/citologia , Masculino , Metformina/farmacologia , Camundongos
16.
J Am Soc Mass Spectrom ; 30(7): 1199-1203, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949967

RESUMO

In this paper, drug-drug chemical interactions between two different aromatic compounds were studied by mass spectrometry. Specifically, we examined non-covalent complexes (NCX) between paclitaxel, a chemotherapeutic compound, and medications widely used in palliative care for depression, psychosis, and anxiety. It is unknown whether psychotropic medications directly interact with paclitaxel. Here, we use a simple and rapid electrospray ionization mass spectrometry in vitro assay, which has been predictive in the case of neuropeptides, to measure the relative strength of non-covalent interactions. This chemical interaction is most likely due to the overlap of aromatic rings of π-orbitals between paclitaxel and five commonly used medications: diazepam, clonozepam, sertraline, fluoxetine, and haloperidol. Molecular modeling illustrates that differences in the stability of the NCXs are likely due to the distance between the aromatic rings present in both the paclitaxel and antidepressant medications. Graphical Abstract.


Assuntos
Ansiolíticos/química , Antidepressivos/química , Antineoplásicos Fitogênicos/química , Paclitaxel/química , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Diazepam/química , Diazepam/farmacologia , Interações de Medicamentos , Fluoxetina/química , Fluoxetina/farmacologia , Haloperidol/química , Haloperidol/farmacologia , Humanos , Modelos Moleculares , Paclitaxel/farmacologia , Sertralina/química , Sertralina/farmacologia , Espectrometria de Massas por Ionização por Electrospray/métodos
17.
Life Sci ; 226: 1-11, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953644

RESUMO

AIM: Fluoxetine (FXT), a selective serotonin reuptake inhibitor (SSRI), is one of the most common psychiatric medications clinically prescribed; while over-produced serotonin may suppress neurite development. The role of major iridoids like geniposide (GPS) and genipin (GNP) from Gardenia jasminoides Ellis fruit (family Rubiaceae) in ameliorating the anti-neurite outgrowth effect of FXT is poorly understood. In this study, the effects of these iridoids on FXT-suppressed neurite outgrowth in Neuro2a neuroblastoma cells were investigated. MAIN METHODS: Neuro2a cells were treated with FXT and GPS. The effect of GPS-FXT co-treatment on neurite outgrowth was observed using inverted phase-contrast microscope imaging system, while neurite outgrowth markers - microtubule-associated protein-2 (MAP2) and growth-associated protein 43 (GAP43) were analyzed using RT-PCR, Western blot and immunofluorescence staining. The transcription factor-cAMP response element binding (CREB), and signaling pathways - mitogen-activated protein kinase (MAPK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) were also analyzed with the help of Western blot. KEY FINDINGS: The results showed that FXT decreased the neurite outgrowth in Neuro2a cells and also downregulated gene and protein expression of MAP2 and GAP43. It also downregulated the protein expression of phosphorylated-CREB, MAPK, and AKT/mTOR signaling pathways. In contrast, GPS counteracted the effects of FXT. GPS-FXT co-treatment increased the percentage of neurite-bearing cells by 3.6-fold at 200 µM as compared to FXT treatment only. SIGNIFICANCE: This study has provided the possible molecular mechanism showing how FXT exerted its detrimental side-effects on the neurite differentiation, and via the same mechanism how GPS attenuated these side effects.


Assuntos
Fluoxetina/farmacologia , Iridoides/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/análise , Proteína GAP-43/análise , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Associadas aos Microtúbulos/análise , Proteínas Quinases Ativadas por Mitógeno , Células-Tronco Neurais/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR
18.
Artigo em Inglês | MEDLINE | ID: mdl-30980840

RESUMO

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10 mg/kg/day; i.p.) and fluoxetine (18 mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3 mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Benzoxazinas/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Bulbo Olfatório/cirurgia , Triazinas/farmacologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Bulbo Olfatório/fisiologia , Receptores de AMPA/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
19.
Biomed Pharmacother ; 114: 108853, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30986624

RESUMO

It is known that users of psychotropic drugs often have weight gain, adverse effects on bone mineral density and osteoporosis, but the molecular basis for these side effects is poorly understood. The aim of this study is to evaluate the effects in vitro of duloxetine (a serotonin and norepinephrine reuptake inhibitor) and fluoxetine (a selective serotonin reuptake inhibitor) on the physiology of human adult stem cells. Adipose-derived stem cells (ADSCs) were isolated and characterized investigating phenotype morphology, expression and frequency of surface markers. Then, a non-toxic concentration of duloxetine and fluoxetine was selected to treat cells during adipogenic and osteogenic differentiation. Stemness properties and the differentiation potential of drug-treated cells were investigated by the quantification of adipogenic and osteogenic markers gene expression and histological staining. The collected data showed that the administration of a daily non-toxic dose of duloxetine and fluoxetine has not directly influenced ADSCs proliferation and their stemness properties. The treatment with duloxetine or fluoxetine did not lead to morphological alterations during adipogenic or osteogenic commitment. However, treatments with the antidepressant showed a slight difference in adipogenic gene expression timing. Furthermore, duloxetine treatment caused an advance in gene expression of early and late osteogenic markers. Fluoxetine instead caused an increase in expression of osteogenic genes compared to untreated cells. In contrast, in pre-differentiated cells, the daily treatment with duloxetine or fluoxetine did not alter the expression profile of adipogenic and osteogenic differentiation. In conclusion, a non-toxic concentration of duloxetine and fluoxetine does not alter the stemness properties of ADSCs and does not prevent the commitment of pre-differentiated ADSCs in adipocytes or osteocyte. Probably, the weight gain and osteoporotic effects associated with the use of psychotropic drugs could be closely related to the direct action of serotonin.


Assuntos
Antidepressivos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Adulto , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cloridrato de Duloxetina/farmacologia , Fluoxetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Osteócitos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacologia , Adulto Jovem
20.
Psychol Trauma ; 11(7): 751-759, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30958014

RESUMO

BACKGROUND: Childhood trauma is associated with the development of depression during adolescence. Prior research suggests that traumatic experiences may result in differential acute treatment outcomes for depressed adolescents. However, the long-term effects of trauma on treatment response remain unclear. METHOD: Participants (N = 318) with a primary diagnosis of major depressive disorder were randomly assigned to 1 of 3 treatment groups: cognitive-behavioral therapy (CBT), fluoxetine (FLX), or their combination (COMB). All participants received 36 weeks of active treatment followed by 1 year of open follow-up. We hypothesized that (a) adolescents without a trauma history would have greater symptom reduction over the course of treatment compared to those with a trauma history and (b) there would be an interaction between trauma history, treatment arm, and time such that adolescents without trauma histories in combination treatment would improve the most rapidly. Linear mixed effects modeling, factorial ANOVAs, and log-linear analyses were used to test these hypotheses. RESULTS: The linear mixed effect model revealed a significant 3-way interaction of time, trauma, and treatment type. In the CBT and COMB groups, adolescents without trauma histories improved more rapidly than traumatized adolescents. In the single-time-point analyses, there were no significant differences between adolescents with trauma histories and those without trauma histories. CONCLUSIONS: Whereas all treatment groups experienced significant reductions in depression regardless of trauma history, adolescents without trauma histories receiving psychotherapy demonstrated more rapid improvements in depression symptom severity. Treatment response did not differ between traumatized and nontraumatized youth at long-term follow-up. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Terapia Cognitivo-Comportamental , Transtorno Depressivo Maior/terapia , Fluoxetina/farmacologia , Trauma Psicológico/terapia , Inibidores de Captação de Serotonina/farmacologia , Adolescente , Terapia Combinada , Comorbidade , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Trauma Psicológico/tratamento farmacológico , Trauma Psicológico/epidemiologia
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