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1.
J Chromatogr A ; 1648: 462215, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000593

RESUMO

A new analyte separation and preconcentration method for the trace determination of antidepressant drugs, Fluoxetine (FLU) and Citalopram (CIT) in urine and wastewaters, was developed based on HPLC-DAD analysis after magnetic solid phase extraction (MSPE). In the proposed method, FLU and CIT were retained on the newly synthetized magnetic sorbent (Fe3O4@PPy-GO) in the presence of buffer (pH 10.0) and then were desorbed into a lower volume of acetonitrile prior to the chromatographic determinations. Before HPLC analysis, all samples were filtered through a 0.45 µm PTFE filter. Experimental parameters such as interaction time, desorption solvent and volume, and pH were studied and optimized in order to establish the detection limit, linearity, enrichment factor and other analytical figures of merit under optimum operation conditions. In the developed method, FLU and CIT were analyzed by diode array detector at the corresponding maximum wavelengths of 227 and 238 nm, respectively, by using an isocratic elution of 60% pH 3.0 buffer, 30% acetonitrile, and 10% methanol. By using the optimum conditions, limit of detections for FLU and CIT were 1.58 and 1.43 ng mL-1, respectively, while the limit of quantifications was 4.82 and 4.71 ng mL-1, respectively. Relative standard deviations (RSD%) for triplicate analyses of model solutions containing 100 ng mL-1 target molecules were found to be less than 5.0 %. Finally, the method was successfully applied to urine (both simulated and real healthy human) and wastewater samples, and quantitative results were obtained in recovery experiments.


Assuntos
Antidepressivos/análise , Cromatografia Líquida/métodos , Citalopram/análise , Fluoxetina/análise , Espectrofotometria Ultravioleta/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análise , Antidepressivos/urina , Citalopram/urina , Fluoxetina/urina , Humanos , Limite de Detecção , Extração em Fase Sólida/métodos , Solventes/química , Poluentes Químicos da Água/urina
2.
J Clin Neurosci ; 88: 163-172, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33992179

RESUMO

The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people's mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.


Assuntos
/tratamento farmacológico , Reposicionamento de Medicamentos , Inibidores de Captação de Serotonina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fluoxetina/uso terapêutico , Humanos , Pandemias
3.
Drug Dev Ind Pharm ; 47(4): 645-653, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33826435

RESUMO

AIM: Fluoxetine (FLX) has become the first-line drug in the pharmacotherapy of patients with depression. However, it has a strong unpleasant bitter taste, leading to the failure to complete the therapy. In this study, FLX is formulated into orodispersible tablets (ODTs) characterized by a fast release with an acceptable taste. METHOD: FLX ODTs were prepared by the complexation of FLX with ß-cyclodextrin (ß-CD) for taste-masking, using different super disintegrants, namely crospovidone (CP), croscarmellose sodium (Ccs), sodium starch glycolate (SSG), and indion. The FLX powder blend is estimated for pre-and post-compression parameters. The selected tablet formulations based upon drug release at 40 s with acceptable release patterns are investigated for accelerated stability testing and comparative in vivo study with a marketed product. RESULTS: It was found that all FLX-powder blends have good flow properties; all the prepared tablets complied with the pharmacopeial requirements for the unity of content, weight, friability, and hardness. Moreover, all the tablets obtained acceptable taste after complexation with ß-CD. The order of release of the drug, regarding super disintegrants used, was as in the following descending order: CP > Ccs > SSG > indion. Accelerated stability study of selected formulation F2 and F6 showed that; there were no considerable changes in physical properties, drug content, and percentage drug release. Furthermore, also the in vivo study proved the effectiveness of FLX ODTs as an antidepressant. CONCLUSION: The results obtained showed a promising potential of the prepared FLX ODTs for treating depression effectively.


Assuntos
Fluoxetina , Paladar , Administração Oral , Depressão , Composição de Medicamentos , Humanos , Solubilidade , Comprimidos
4.
Chemosphere ; 277: 130169, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33794438

RESUMO

Antidepressants in coastal waters may affect ontogeny of predatory behaviour in cuttlefish, which may, as a result, affect growth of newly-hatched cuttlefish. We investigated the effects of two of the most prescribed antidepressants, fluoxetine (FLX) and venlafaxine (VEN) in environmentally realistic concentrations on the predatory behaviour of hatchlings of Sepia officinalis. Newly-hatched cuttlefish were exposed from 1 h (i.e., day 1) to 5 days after hatching to either FLX alone (5 ng·L-1) or combined with VEN (2.5 ng·L-1 or 5 ng·L-1 each) to simulate an environmentally realistic exposure scenario. Their predatory behaviour was analysed through several parameters: prey detection, feeding motivation and success in catching the prey. All parameters improved in control animals over the first five days. The combination of FLX and VEN at 5 ng·L-1 each altered the predatory behaviour of the hatchlings by increasing the latency before attacking the prey, i.e., reducing feeding motivation, as well as by reducing the number of successful attacks. The changes in predatory behaviour tended to reduce food intake and affected growth significantly at 28 days post-hatching. Exposures to either FLX at 5 ng·L-1 or FLX and VEN in mixture at 2.5 ng·L-1 each tended to produce similar effects, even though they were not statistically significant. It is likely that the antidepressants affect maturation of the predatory behaviour and/or learning processes associated with the development of this behaviour. The slightest delay in maturation processes may have detrimental consequences for growth and population fitness.


Assuntos
Fluoxetina , Poluentes Químicos da Água , Animais , Decapodiformes , Fluoxetina/toxicidade , Comportamento Predatório , Cloridrato de Venlafaxina/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
5.
Eur J Pharmacol ; 900: 174055, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33775645

RESUMO

In patients with obstructive jaundice, the cardiovascular system exhibits hypotension and vascular hyporeactivity. Most norepinephrine is taken up through the neuronal norepinephrine transporter (NET), which is implicated in cardiovascular diseases. A previous study demonstrated that pharmacological NET inhibition could increase resting blood pressure. However, the role of NETs in vascular hyporeactivity induced by obstructive jaundice is poorly understood. This study used the NET inhibitor nisoxetine and a rat model of bile duct ligation (BDL) to investigate whether NET is associated with BDL-induced vascular hyporeactivity. Rats were injected with nisoxetine via the tail vein for 7 consecutive days after BDL. Samples of the superior cervical sympathetic ganglion (SCG) and thoracic aortic rings were processed for investigations. Our results showed that NET expression in the SCG was significantly increased after BDL. Nisoxetine prevented the augmentation of NET expression, increased α1-adrenoceptor activation, and enhanced the weakened contractile responses of thoracic aortic rings after BDL. Our study demonstrates that nisoxetine plays a protective role in BDL-induced vascular hyporeactivity through increased α1-adrenoceptor activation in rats.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Catecolaminas , Icterícia Obstrutiva/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Ductos Biliares , Bilirrubina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Gânglios Simpáticos/efeitos dos fármacos , Icterícia Obstrutiva/fisiopatologia , Ligadura , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
6.
Environ Pollut ; 278: 116777, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33689951

RESUMO

A recent surge in the use and abuse of diverse prescribed psychotic and illicit drugs necessitates the surveillance of drug residues in source water and the associated ecological impacts of chronic exposure to the aquatic organism. Thirty-six psychotic and illicit drug residues were determined in discharged wastewater from two centralized municipal wastewater treatment facilities and two wastewater receiving creeks for seven consecutive days in Kentucky. Zebrafish (Danio rerio) larvae were exposed to the environmental relevant mixtures of all drug residues, all illicit drugs, and all prescribed psychotic drugs. The extracted RNA from fish homogenates was sequenced, and differentially expressed sequences were analyzed for known or predicted nervous system expression, and screened annotated protein-coding genes to the true environmental cocktail mixture. Illicit stimulant (cocaine and one metabolite), opioids (methadone, methadone metabolite, and oxycodone), hallucinogen (MDA), benzodiazepine (oxazepam and temazepam), carbamazepine, and all target selective serotonin reuptake inhibitors including sertraline, fluoxetine, venlafaxine, and citalopram were quantified in 100% of collected samples from both creeks. The high dose cocktail mixture exposure group revealed the largest group of differentially expressed genes: 100 upregulated and 77 downregulated (p ≤ 0.05; q ≤ 0.05). The top 20 differentially expressed sequences in each exposure group comprise 82 unique transcripts corresponding to 74% annotated genes, 7% non-coding sequences, and 19% uncharacterized sequences. Among 61 differentially expressed sequences that corresponded to annotated protein-coding genes, 23 (38%) genes or their homologs are known to be expressed in the nervous system of fish or other organisms. Several of the differentially expressed sequences are associated primarily with the immune system, including several major histocompatibility complex class I and interferon-induced proteins. Interleukin-1 beta (downregulated in this study) abnormalities are considered a risk factor for psychosis. This is the first study to assess the contributions of multiple classes of psychotic and illicit drugs in combination with developmental gene expression.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Fluoxetina , Larva , Inibidores de Captação de Serotonina , Poluentes Químicos da Água/toxicidade
7.
Biomed Pharmacother ; 138: 111437, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33691249

RESUMO

Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients with Coronavirus Disease 2019 (COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e. knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic, anti-inflammatory effects. Our results demonstrate a critical role for IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Receptor gp130 de Citocina/genética , Síndrome da Liberação de Citocina/tratamento farmacológico , Fluoxetina/uso terapêutico , Subunidade p50 de NF-kappa B/genética , Anti-Inflamatórios/farmacologia , Fluoxetina/farmacologia , Humanos
8.
Sci Rep ; 11(1): 5890, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723270

RESUMO

To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 µg/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.


Assuntos
Antivirais/farmacologia , Fluoxetina/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/virologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Antivirais/uso terapêutico , Linhagem Celular , Células Cultivadas , Fluoxetina/uso terapêutico , Humanos , Pulmão/patologia , Inibidores de Captação de Serotonina/uso terapêutico , Replicação Viral/efeitos dos fármacos
9.
Medicine (Baltimore) ; 100(10): e24968, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725863

RESUMO

BACKGROUND: Poststroke depression is a common secondary mental disorder after stroke, which increases the recurrence rate and mortality rate after stroke and hinders the recovery of function. As a combination therapy, simple acupuncture combined with fluoxetine has achieved good clinical effect, but there is a lack of evidence-based medicine. The purpose of this study is to evaluate the efficacy and safety of acupuncture combined with fluoxetine in the treatment of poststroke depression by meta-analysis. METHODS: Search Chinese and English databases: China national knowledge infrastructure, VP information Chinese Journal Service Platform, Wanfang, the China Biomedical Database, PubMed, Embase, the Cochrane Library, and web of science. A randomized controlled trial of simple acupuncture combined with fluoxetine in the treatment of poststroke depression will be selected. The retrieval time is of the establishment of the database in January 2021. Selected literature is extracted and deleted by 2 researchers, and the quality of the included literature is evaluated. The included literature is analyzed by Meta with RevMan5.3 software. RESULTS: In this study, the efficacy and safety of acupuncture combined with fluoxetine in the treatment of post-stroke depression are evaluated by Hamilton Depression scale (HAMD) and its reduction rate, Treatment Emergency Symptom Scale, Self-rating Depression Scale, and Activities of Daily living scale. CONCLUSION: This study will provide reliable evidence-based evidence for the clinical application of acupuncture combined with fluoxetine in the treatment of post-stroke depression. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/5J896.


Assuntos
Terapia por Acupuntura , Depressão/terapia , Fluoxetina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Acidente Vascular Cerebral/complicações , Atividades Cotidianas , Terapia Combinada/métodos , Depressão/diagnóstico , Depressão/etiologia , Depressão/psicologia , Humanos , Metanálise como Assunto , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/psicologia , Reabilitação do Acidente Vascular Cerebral/métodos , Revisões Sistemáticas como Assunto , Resultado do Tratamento
10.
Cochrane Database Syst Rev ; 3: CD008591, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661528

RESUMO

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Afetivo Sazonal/tratamento farmacológico , Adulto , Antidepressivos de Segunda Geração/efeitos adversos , Viés , Citalopram/efeitos adversos , Citalopram/uso terapêutico , Cloridrato de Duloxetina/efeitos adversos , Cloridrato de Duloxetina/uso terapêutico , Feminino , Fluoxetina/efeitos adversos , Fluoxetina/uso terapêutico , Humanos , Masculino , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Estudos Observacionais como Assunto , Fototerapia , Placebos/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Reboxetina/uso terapêutico , Transtorno Afetivo Sazonal/terapia , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , Resultado do Tratamento
11.
Aquat Toxicol ; 234: 105808, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33774504

RESUMO

Juvenile crabs of Carcinus maenas thrive in coastal waters reputed to be the receptacle of continental pollution. Amongst the many pollutants encountered, antidepressants, such as fluoxetine (FLX) and venlafaxine (VEN), often detected at the ng•L-1 range, are particularly worrying because of their action on the levels of monoamines, such as serotonin, noradrenaline and dopamine. In crustaceans, those monoamines are involved in colour change through their action on neuropeptide hormones. In addition, they are known to have a role in different behaviours, such as locomotion. Both colour change and locomotion are strategies used by juvenile crabs to hide and escape from predators. To investigate if the presence of antidepressants may alter behaviours of ecological importance, juvenile crabs were exposed to environmentally realistic concentrations of either 5 ng•L-1 of FLX alone or in combination with VEN at 5 ng•L-1. The ability to change colour depending on the environment and the locomotor activity of juvenile crabs were monitored weekly over 25 days. Animals exposed to antidepressants displayed a different pattern of colour change than the controls, especially those exposed to the combination of FLX and VEN at 5 ng•L-1 each, and were less efficient to adapt to their environment, i.e., they were not as pale and not as dark as controls or crabs exposed to FLX at 5 ng•L-1. Moreover, juvenile crabs exposed to the combination of antidepressants exhibited an enhanced locomotor activity throughout the exposure period with a higher velocity and distance moved as well as more time spend moving. The alteration of cryptic behaviours, such as colour change and locomotion by antidepressants persistently present in marine environment at low concentrations may have an impact on the survival of juvenile of C. maenas on the long term.


Assuntos
Antidepressivos/toxicidade , Braquiúros/fisiologia , Locomoção/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Braquiúros/efeitos dos fármacos , Braquiúros/crescimento & desenvolvimento , Cor , Fluoxetina/toxicidade , Cloridrato de Venlafaxina/toxicidade
12.
Proc Biol Sci ; 288(1944): 20202294, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33563120

RESUMO

Environmental contamination by pharmaceuticals is global, substantially altering crucial behaviours in animals and impacting on their reproduction and survival. A key question is whether the consequences of these pollutants extend beyond mean behavioural changes, restraining differences in behaviour between individuals. In a controlled, two-year, multigenerational experiment with independent mesocosm populations, we exposed guppies (Poecilia reticulata) to environmentally realistic levels of the ubiquitous pollutant fluoxetine (Prozac). Fish (unexposed: n = 59, low fluoxetine: n = 57, high fluoxetine: n = 58) were repeatedly assayed on four separate occasions for activity and risk-taking behaviour. Fluoxetine homogenized individuals' activity, with individual variation in populations exposed to even low concentrations falling to less than half that in unexposed populations. To understand the proximate mechanism underlying these changes, we tested the relative contribution of variation within and between individuals to the overall decline in individual variation. We found strong evidence that fluoxetine erodes variation in activity between but not within individuals, revealing the hidden consequences of a ubiquitous contaminant on phenotypic variation in fish-likely to impair adaptive potential to environmental change.


Assuntos
Poecilia , Poluentes Químicos da Água , Animais , Comportamento Animal , Poluição Ambiental , Fluoxetina/efeitos adversos , Individualidade , Poluentes Químicos da Água/toxicidade
13.
Phytomedicine ; 84: 153482, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33611213

RESUMO

INTRODUCTION: Approximately 300 million people worldwide suffer from depression. The COVID-19 crisis may dramatically increase these numbers. Severe side effects and resistance development limit the use of standard antidepressants. The steroidal lactone withanolide A (WA) from Withania somnifera may be a promising alternative. Caenorhabditis elegans was used as model to explore WA's anti-depressive and anti-stress potential. METHODS: C. elegans wildtype (N2) and deficient strains (AQ866, DA1814, DA2100, DA2109 and MT9772) were used to assess oxidative, osmotic or heat stress as measured by generation of reactive oxygen species (ROS), determination of lifespan, and mRNA expression of serotonin receptor (ser-1, ser-4, ser-7) and serotonin transporter genes (mod-5). The protective effect of WA was compared to fluoxetine as clinically established antidepressant. Additionally, WA's effect on lifespan was determined. Furthermore, the binding affinities and pKi values of WA, fluoxetine and serotonin as natural ligand to Ser-1, Ser-4, Ser-7, Mod-5 and their human orthologues proteins were calculated by molecular docking. RESULTS: Baseline oxidative stress was higher in deficient than wildtype worms. WA and fluoxetine reduced ROS levels in all strains except MT9772. WA and fluoxetine prolonged survival times in wildtype and mutants under osmotic stress. WA but not fluoxetine increased lifespan of all heat-stressed C. elegans strains except DA2100. Furthermore, WA but not fluoxetine extended lifespan in all non-stressed C. elegans strains. WA also induced mRNA expression of serotonin receptors and transporters in wildtype and mutants. WA bound with higher affinity and lower pKi values to all C. elegans and human serotonin receptors and transporters than serotonin, indicating that WA may competitively displaced serotonin from the binding pockets of these proteins. CONCLUSION: WA reduced stress and increased lifespan by ROS scavenging and interference with the serotonin system. Hence, WA may serve as promising candidate to treat depression.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Receptores de Serotonina/genética , Vitanolídeos/farmacologia , Animais , Caenorhabditis elegans/fisiologia , Fluoxetina/farmacologia , Técnicas de Inativação de Genes , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Serotonina/metabolismo , Withania/química
14.
Environ Pollut ; 276: 116738, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33611201

RESUMO

Low doses of neuroactive chemicals end up in the environment and disrupt behaviour of non-target organisms. Although a whole range of studies have documented pollutant-induced changes in behaviour, natural daily variability in behaviour is rarely taken into account. This is surprising because biological rhythms may affect the outcome of experiments, are adaptive and are expected to be sensitive to neurochemical exposure. Here, we exploit daily behavioural variation in the fish model Nothobranchius furzeri to examine if behavioural effects of chronic exposure (74 days) to an environmentally relevant level (28 ng/L) of the neurochemical fluoxetine depend on the time of day. Fluoxetine exposure induced an increase in anxiety-related behaviour that was slightly more pronounced in the evening compared to the morning. Moreover, open-field locomotor activity was disrupted and daily patterns in activity lifted upon exposure to the compound. These results imply that short-term behavioural variability should be considered both to standardise ecological risk assessment of neuroactive chemicals as well as to better understand the environmental impact of such compounds in aquatic ecosystems.


Assuntos
Ciprinodontiformes , Poluentes Químicos da Água , Animais , Ecossistema , Ecotoxicologia , Fluoxetina , Poluentes Químicos da Água/toxicidade
15.
Neuroscience ; 459: 85-103, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524494

RESUMO

The synaptogenic hypothesis of major depressive disorder implies that preventing the onset of depressive-like behavior also prevents the loss of hippocampal spine synapses. By applying the psychoactive drugs, diazepam and fluoxetine, we investigated whether blocking the development of helpless behavior by promoting stress resilience in the rat learned helplessness paradigm is associated with a synaptoprotective action in the hippocampus. Adult ovariectomized and intact female Sprague-Dawley rats (n = 297) were treated with either diazepam, fluoxetine, or vehicle, exposed to inescapable footshocks or sham stress, and tested in an active escape task to assess helpless behavior. Escape-evoked corticosterone secretion, as well as remodeling of hippocampal spine synapses at a timepoint representing the onset of escape testing were also analyzed. In ovariectomized females, treatment with diazepam prior to stress exposure prevented helpless behavior, blocked the loss of hippocampal spine synapses, and muted the corticosterone surge evoked by escape testing. Although fluoxetine stimulated escape performance and hippocampal synaptogenesis under non-stressed conditions, almost all responses to fluoxetine were abolished following exposure to inescapable stress. Only a much higher dose of fluoxetine was capable of partly reproducing the strong protective actions of diazepam. Importantly, these protective actions were retained in the presence of ovarian hormones. Our findings indicate that stress resilience is associated with the preservation of spine synapses in the hippocampus, raising the possibility that, besides synaptogenesis, hippocampal synaptoprotection is also implicated in antidepressant therapy.


Assuntos
Transtorno Depressivo Maior , Desamparo Aprendido , Animais , Modelos Animais de Doenças , Feminino , Fluoxetina/farmacologia , Hipocampo , Ratos , Ratos Sprague-Dawley
16.
Neurosci Lett ; 748: 135734, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33596470

RESUMO

Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal's sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress.


Assuntos
Fluoxetina/farmacologia , Privação Materna , Dor/fisiopatologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Dor/tratamento farmacológico , Ratos Wistar
17.
Sci Total Environ ; 776: 145945, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33639467

RESUMO

Nowadays the presence of pharmaceuticals in the environment is a real problem. Ending up in aquatic environments they negatively affect non-target organisms. Considering the limited studies on the negative effects of pharmaceuticals in amphibians, a better understanding of the mechanisms underlying the sub-lethal effects of drug mixtures in wildlife is an urgent call. Representing particularly vulnerable organisms currently at risk of extinction, amphibians are perfect non-target organisms to explore the consequences of pharmaceuticals during sensitive life-stages. To address this existing research gap, the effects of two drugs, the antidepressant fluoxetine and the anti-inflammatory ibuprofen, as well as their combination has been studied. Tadpoles of Bufo bufo were exposed for seven days to two environmentally realistic concentrations of fluoxetine, ibuprofen and their mixture. The development, behavior and erythron profile were then evaluated as endpoints of exposure response. Both drugs negatively affected tadpoles' growth and development by significantly delayed their time to metamorphosis and reduced body weight. Behaviors were also impaired with a significant increase of unresponsiveness to different stimuli. Mutagenic analysis of blood revealed a significant increase in the frequency of cellular and nuclear abnormalities. Given the complexity of systems and functions affected, our work confirms the toxicological potential of fluoxetine and ibuprofen in B. bufo tadpoles by emphasizing their role as tadpole development delayers and erythrocyte apoptosis-inducers. To our knowledge, this is the first study trying to elucidate the potentially toxic effects of a mixture of an antidepressant with a non-steroidal anti-inflammatory drug using bullfrog tadpole as model organism. Both drugs interacted in impairing development and fitness in tadpoles, which might affect long-term species perpetuation and population dynamic. More in-depth research is needed to elucidate the nature of interaction and molecular mechanisms of mixed pharmaceutical compounds on non-targeted organisms.


Assuntos
Bufo bufo , Poluentes Químicos da Água , Animais , Apoptose , Fluoxetina/toxicidade , Ibuprofeno/toxicidade , Larva , Poluentes Químicos da Água/toxicidade
19.
Environ Toxicol Pharmacol ; 83: 103586, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33460806

RESUMO

Some studies have suggested possible estrogen actions for antidepressants such as fluoxetine. However, the specific molecular mechanisms remain unclear. In this study, the molecular mechanism of fluoxetine-induced the proliferation of breast cancer SKBR3 and MCF-7 cells was evaluated by detecting ERα and GPR30-mediated ERK and PI3K/AKT signals. We found that low concentrations of fluoxetine upregulated the expression of GPR30, ERα, CyclinD1, and C-MYC proteins, as well as elevated the phosphorylation of ERK and AKT. The phosphorylation of ERK and AKT decreased when the cells were pretreated with ERα inhibitor ICI, GPR30 inhibitor G15, and PI3K inhibitor WM prior to fluoxetine exposure. The addition of these inhibitors also attenuated the fluoxetine-induced cell proliferation. These findings indicated that fluoxetine activated the PI3K/AKT and ERK signaling cascades via GPR30 to derive the cell proliferation. It suggests that fluoxetine has the potential to exert estrogen actions via GPR30.


Assuntos
Amitriptilina/farmacologia , Antidepressivos/farmacologia , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Estrogênios/farmacologia , Fluoxetina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
20.
Zool Res ; 42(1): 28-42, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33420763

RESUMO

Depression is a prevalent mental disorder that is associated with aging and contributes to increased mortality and morbidity. The overall prevalence of geriatric depression with clinically significant symptoms is currently on the rise. Recent studies have demonstrated that altered expressions of long non-coding RNAs (lncRNAs) in the brain affect neurodevelopment and manifest modulating functions during the depression. However, most lncRNAs have not yet been studied. Herein, we analyzed the transcriptome of dysregulated lncRNAs to reveal their expressions in a mouse model exhibiting depressive-like behaviors, as well as their corresponding response following antidepressant fluoxetine treatment. A chronic unpredictable mild stress (CUMS) mouse model was applied. A six-week fluoxetine intervention in CUMS-induced mice attenuated depressive-like behaviors. In addition, differential expression analysis of lncRNAs was performed following RNA-sequencing. A total of 282 lncRNAs (134 up-regulated and 148 down-regulated) were differentially expressed in CUMS-induced mice relative to non-stressed counterparts ( P<0.05). Moreover, 370 differentially expressed lncRNAs were identified in CUMS-induced mice after fluoxetine intervention. Gene Ontology (GO) analyses showed an association between significantly dysregulated lncRNAs and protein binding, oxygen binding, and transport activity, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these dysregulated lncRNAs might be involved in inflammatory response pathways. Fluoxetine effectively ameliorated the symptoms of depression in CUMS-induced mice by regulating the expression of lncRNAs in the hippocampus. The findings herein provide valuable insights into the potential mechanism underlying depression in elderly people.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Fluoxetina/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Antidepressivos de Segunda Geração/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Longo não Codificante/genética , Estresse Psicológico
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