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1.
Behav Brain Res ; 437: 114128, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36174841

RESUMO

While SSRIs are the current first-line pharmacotherapies against post-traumatic stress disorder (PTSD), they suffer from delayed onset of efficacy and low remission rates. One solution is to combine SSRIs with other treatments. Neuronal nitric oxide synthase (nNOS) has been shown to play a role in serotonergic signaling, and there is evidence of synergism between nNOS modulation and SSRIs in models of other psychiatric conditions. Therefore, in this study, we combined subchronic fluoxetine (Flx) with 7-nitroindazole (NI), a selective nNOS inhibitor, and evaluated their efficacy against anxiety-related behavior in an animal model of PTSD. We used the underwater trauma model to induce PTSD in rats. Animals underwent the open field (OFT) and elevated plus maze tests on days 14 (baseline) and 21 (post-treatment) after PTSD induction to assess anxiety-related behaviors. Between the two tests, the rats received daily intraperitoneal injections of 10 mg/kg Flx or saline, and were injected intraperitoneally before the second test with either 15 mg/kg NI or saline. The change in behaviors between the two tests was compared between treatment groups. Individual treatment with both Flx and NI had anxiogenic effects in the OFT. These effects were associated with modest increases in cFOS expression in the hippocampus. Combination therapy with Flx + NI did not show any anxiogenic effects, while causing even higher expression levels of cFOS. In conclusion, addition of NI treatment to subchronic Flx therapy accelerated the abrogation of Flx's anxiogenic properties. Furthermore, hippocampal activity, as evidenced by cFOS expression, was biphasically related to anxiety-related behavior.


Assuntos
Ansiolíticos , Inibidores Enzimáticos , Óxido Nítrico Sintase Tipo I , Inibidores de Captação de Serotonina , Transtornos de Estresse Pós-Traumáticos , Animais , Ratos , Ansiedade/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico
2.
Mol Cell Endocrinol ; 559: 111783, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36198363

RESUMO

Selective serotonin reuptake inhibitors (SSRI) are the most used antidepressants. However, up to 80% of women taking SSRI suffer from sexual dysfunction. We investigated the effects of fluoxetine (Prozac®) (low and high dose, n = 6-7/group) on reproductive function and the regulation of the estrous cycle. All mice treated with high dose of fluoxetine had interruption of estrous cycles within a few days after onset of treatment. When treated for 14 days, mice in the high dose group had fewer CL, often lack of any CL, and antral follicles. Uterine expression of estrogen receptor alpha, G-protein coupled estrogen receptor, and steroidogenesis enzymes were upregulated in the high dose group. Nevertheless, decreased expression of connexin 43 and alkaline phosphatase and increased expression of insulin-like growth factor-binding protein 3 and monoamine oxidase A are consistent with decreased estrogen signaling and the decreased uterine weight. Taken together, fluoxetine modulates estrogen synthesis/signaling and dysregulates estrous cycles.


Assuntos
Ciclo Estral , Fluoxetina , Camundongos , Feminino , Animais , Fluoxetina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Antidepressivos/farmacologia , Útero/metabolismo , Estrogênios/farmacologia , Estrogênios/metabolismo
3.
Behav Brain Res ; 436: 114114, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36116737

RESUMO

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal depression but prenatal SSRI exposure itself may be a risk factor for autism in offspring. The present study investigated in C57BL/6J pregnant mice whether restraint stress (G4-18) and/or treatment with the SSRI fluoxetine (G8-18) affects autism-related behaviors and hippocampal synaptic plasticity in male and female offspring. The findings indicate that restraint stress reduces preference for sucrose reward in pregnant dams that is reversed by fluoxetine. In adult male offspring, combined prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning. In adult female offspring, the prenatal experiences did not affect self-grooming, but restraint stress alone or SSRI exposure alone impaired spatial reversal learning. Prenatal stress reduced anxiety-related behavior in male and female offspring. Further, LTP induced by theta-burst stimulation of Schaffer-commissural afferents in field CA1 was significantly reduced in female offspring exposed to prenatal stress alone or combination with fluoxetine. Together, these findings suggest that exposure to prenatal stress, SSRI treatment or the combination differentially affects male and female offspring in autism-like behaviors and synaptic plasticity.


Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Fluoxetina/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Gravidez , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/farmacologia , Sacarose/farmacologia
4.
J Ethnopharmacol ; 300: 115719, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36126781

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, the dried stigma of Crocus sativus L., has a long history of use in the treatment of depression in traditional Chinese medicine and Islamic medicine. The unique aroma of saffron, primarily derived from its volatile oil, has been widely used by folk to mitigate anxiety and depression via sniffing because the aroma of saffron has a pleasant and invigorating effect. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect and the underlying mechanism of saffron essential oil (SEO) in mice exposed to chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: In this study, compounds of SEO were identified using gas chromatography-mass spectrometry analysis, while network pharmacology was used to predict potential active compounds, antidepressant targets, and related signaling pathways of SEO. The CUMS depression model was further used to explore the therapeutic effect and possible mechanism of SEO. During the modeling period, mice were regularly administered fluoxetine (3.6 mg/kg, i.g.) or diluted SEO (2%, 4%, and 6% SEO, inhalation). The antidepressant and neuroprotective effects of SEO were evaluated by behavior tests (the open field test, the sucrose preference test, the tail suspension test, and the forced swimming test), hematoxylin-eosin staining, and Nissl staining. The enzyme-linked immunosorbent assay kits were used to measure dopamine (DA), 5-serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and γ-aminobutyric acid (GABA) levels in serum. The relative abundance of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B in the hippocampus was determined using western blot (WB). RESULTS: According to the network pharmacology analysis, seven active SEO compounds mediated 113 targets related to depression treatment, most of which were enriched in the 5-HT synapse, calcium signaling pathway, and cAMP signaling pathway. In vivo experiments indicated that fluoxetine and SEO improved depression-like behaviors in depressed mice. The levels of 5-HT, DA, BDNF, and GABA in serum increased significantly. Histopathological examinations revealed that fluoxetine and SEO ameliorated neuronal damage in the hippocampus. WB analysis showed that the relative expressions of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B were significantly higher in the fluoxetine and SEO groups than in the CUMS group. CONCLUSION: Overall, these findings suggest that SEO significantly alleviates the depressive symptoms in CUMS exposed mice and partially restores hippocampal neuronal damage. Meanwhile, the best efficacy was observed in 4% SEO. Furthermore, the antidepressant mechanism of SEO is primarily dependent on the regulation of the MAPK-CREB1-BDNF signaling pathway.


Assuntos
Crocus , Fármacos Neuroprotetores , Óleos Voláteis , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Crocus/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Fluoxetina/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hipocampo , Sistema de Sinalização das MAP Quinases , Camundongos , Fármacos Neuroprotetores/farmacologia , Óleos Voláteis/metabolismo , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Serotonina/metabolismo , Transdução de Sinais , Estresse Fisiológico , Estresse Psicológico/tratamento farmacológico , Sacarose/metabolismo , Sacarose/farmacologia , Ácido gama-Aminobutírico/metabolismo
5.
Zool Res ; 44(1): 30-42, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36266933

RESUMO

Fluoxetine (Prozac™) is the only antidepressant approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in children. Despite its considerable efficacy as a selective serotonin reuptake inhibitor, the possible long-term effects of fluoxetine on brain development in children are poorly understood. In the current study, we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques (Macaca mulatta) one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling. We identified several differences in protein expression and phosphorylation in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) that correlated with impulsivity in animals, suggesting that the GABAergic synapse pathway may be affected by fluoxetine treatment. Biomarkers in combination with the identified pathways contribute to a better understanding of the mechanisms underlying the chronic effects of fluoxetine after discontinuation in children.


Assuntos
Transtorno Depressivo Maior , Fluoxetina , Estados Unidos , Animais , Fluoxetina/farmacologia , Macaca mulatta , Inibidores de Captação de Serotonina/farmacologia , Proteômica , Biomarcadores
6.
Behav Brain Res ; 437: 114146, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36202146

RESUMO

Some diabetes patients develop depression, the main treatment for which is antidepressants. Pharmacological interactions between insulin and antidepressants (e.g., fluoxetine) are controversial in the literature. Some authors reported hypoglycemic actions of fluoxetine, whereas others reported antidepressant-like actions. In healthy rats, insulin produces an antidespair-like action in rats through an increase in locomotor and exploratory activity, but differences in actions of insulin and fluoxetine on neuronal activity are unknown. The present study evaluated Wistar healthy rats that were treated with saline, insulin, fluoxetine, or fluoxetine + insulin for 3 days (short-term) or 21 days (long-term). The model consisted of electrical stimulation of the lateral septal nucleus (LSN) while we performed single-unit extracellular response recordings in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Stimulation of the LSN produced an initial brief excitatory paucisynaptic response and then a long-lasting inhibitory afterdischarge in the PL and IL. Treatment with saline and fluoxetine, but not insulin, minimally affected the paucisynaptic response. Differences were found in LSN-IL responsivity. The inhibitory afterdischarge was clearly enhanced in the long-term fluoxetine group but not by insulin alone or fluoxetine + insulin. These findings suggest that insulin produces some actions that are opposite to fluoxetine on LSN-mPFC connection responsivity, with no synergistic actions between the actions of insulin and fluoxetine.


Assuntos
Núcleos Septais , Animais , Ratos , Fluoxetina/farmacologia , Insulina/farmacologia , Ratos Wistar , Córtex Pré-Frontal/fisiologia , Antidepressivos/farmacologia
7.
Sci Total Environ ; 857(Pt 2): 159486, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36257440

RESUMO

Fluoxetine is one of the most studied and detected selective serotonin reuptake inhibitors in the aquatic environment, found at concentrations ranging from ng/L to µg/L. Its presence in this environment can induce effects on aquatic organisms that may compromise their fitness. Several experimental studies have demonstrated that fluoxetine can induce neurotoxicity, genetic and biochemical changes, and cause behavioral dysfunction in a wide range of fish species. However, contradictory results can be found. There is thus the need for a comprehensive review of the current state of knowledge on the effects of fluoxetine on fish at different levels of biological organization, highlighting inclusive patterns and discussing the potential causes for the contradictory results, that can be found in the available literature. This review also aims to explore and identify the main gaps in knowledge and areas for future research. We conclude that environmentally relevant concentrations of fluoxetine (e.g., from 0.00345 µg/L) produced adverse effects and often this concentration range is not addressed in conventional environmental risk assessment strategies. Its environmental persistence and ionizable properties reinforce the need for standardized testing with representative aquatic models, targeting endpoints sensitive to the specific mode of action of fluoxetine, in order to assess and rank its actual environmental risk to aquatic ecosystems.


Assuntos
Fluoxetina , Poluentes Químicos da Água , Animais , Fluoxetina/toxicidade , Ecossistema , Poluentes Químicos da Água/toxicidade , Inibidores de Captação de Serotonina/toxicidade , Organismos Aquáticos , Peixes
8.
Sci Total Environ ; 856(Pt 2): 159042, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36174704

RESUMO

The role of serotonin in Daphnia magna phototactic and locomotor behavior was assessed using reverse genetics and pharmacological treatments with serotonin and fluoxetine. The study was conducted with four clones: the wild type clone and three CRISPR D. magna ones with mutations in the tryptophan hydrolase gene (TRH) that is involved in serotonin synthesis. These included clones TRHA- and TRHB- with mutations in both alleles that lack serotonin and the mono-allelic mutant TRH+, that has serotonin. Obtained results indicated that animals lacking serotonin showed an increased negative phototactism and locomotor activity upon light stimuli and a reduced response to fish kairomones relative to the wild type and TRH+ individuals. Exposure to exogenous serotonin re-established the phototactism and locomotor activity of TRH- individuals to those of the wild type but did not affect phototactic responses to fish kairomones. Unexpectedly, fluoxetine was able to modify locomotor activity and phototactic behavior against fish kairomones in TRH- individuals lacking serotonin, and also it increased the concentrations of acethylcholine and GABA in exposed animals, which support the argument that fluoxetine may also affect other neurological pathways.


Assuntos
Daphnia , Serotonina , Animais , Daphnia/fisiologia , Fluoxetina , Fototaxia , Peixes , Feromônios , Triptofano
9.
Int Immunopharmacol ; 113(Pt A): 109417, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36461606

RESUMO

AIM: To determine the neuroprotective effects of fluoxetine on depression-like and motor behaviors in rats treated with lipopolysaccharide (LPS) and the mechanisms involved. METHODS: A rat model of depression in Parkinson's disease (dPD) was established by administering LPS (0.5 mg/kg, i.p.) for 4 days. The sucrose preference test (SPT), open field test (OFT), and rotarod test evaluated depression-like and motor behaviors. White matter fiber integrity and intrinsic activity in the brain were assessed using magnetic resonance imaging. For pathological and molecular expression detection, hematoxylin-eosin staining, immunohistochemistry, Luminex technology, western blotting, and quantitative real-time PCR were used. RESULTS: Fluoxetine increased the sucrose preference in the SPT, the horizontal and center distances in the OFT, and the standing time in the rotarod test. Fluoxetine also improved intrinsic activities and white matter fiber damage in the brain, increased c-Fos expression, reduced Iba-1 expression in the prefrontal cortex, hippocampus, and substantia nigra, and increased TH expression in the substantia nigra. Fluoxetine reduced the concentration of inflammatory cytokines (IL-1α, IL-6, TNF-α, and IFN-γ). The gene and protein expression of Notch1, Jagged1, Hes1, and Hes5 were significantly lower than the LPS group after treatment with fluoxetine. CONCLUSION: Fluoxetine plays neuroprotective effects in relieving LPS-induced depression-like and motor behaviors. The underlying mechanisms may be related to inhibiting microglial activation, regulating the Notch signaling pathway, and inhibiting the inflammatory response.


Assuntos
Lipopolissacarídeos , Fármacos Neuroprotetores , Animais , Ratos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fluoxetina/uso terapêutico , Doenças Neuroinflamatórias , Sacarose , Transdução de Sinais
10.
J. Health Biol. Sci. (Online) ; 10(1): 1-12, 01/jan./2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1382369

RESUMO

Objective: this systematic review aims to compile literature data on the antimicrobial action of Selective Serotonin Reuptake Inhibitors (SSRI). Methods: To this end, the articles in this review were searched in the PubMed database between the years 2010 to 2020, using terms found in MESH as descriptors. The PRISMA flow diagram was used to analyze the process flow of the research. Later, inclusion and exclusion criteria and eligibility for data extraction and statistical analysis were applied. Results: Thus, of 252 articles found, 13 were used for this systematic review. The period in which there were more publications was in 2016-2017. All articles demonstrated the antimicrobial activity of ISRS, such as sertraline, fluoxetine, and paroxetine, in addition to their synergistic activity with some antifungals and antibacterial. Conclusion: With this, it could be concluded that the repositioning of non-antibiotic drugs that have antimicrobial activity is a promising alternative for the scientific community and, in the future, in clinical practice


Objetivo: compilar dados da literatura sobre a ação antimicrobiana dos Inibidores Seletivos de Recaptação de Serotonina (ISRS). Métodos: os artigos desta revisão foram pesquisados na base de dados PubMed, entre os anos de 2010 a 2020, utilizando, como descritores, termos encontrados no MESH. O fluxograma PRISMA foi utilizado para analisar o fluxo do processo da pesquisa. Posteriormente, foram aplicados os critérios de inclusão e exclusão e de elegibilidade para extração de dados e análise estatística. Resultados: dos 252 artigos encontrados, 13 foram utilizados para esta revisão sistemática. O período em que houve mais publicações foi em 2016-2017. Todos os artigos demonstraram a atividade antimicrobiana do ISRS, como sertralina, fluoxetina e paroxetina, além de sua atividade sinérgica com alguns antifúngicos e antibacterianos. Conclusão: o reposicionamento de medicamentos não antibióticos que possuam atividade antimicrobiana é uma alternativa promissora para a comunidade científica e, futuramente, na prática clínica.


Assuntos
Inibidores de Captação de Serotonina , Antibacterianos , Antifúngicos , Bactérias , Serotonina , Fluoxetina , Inibidores de Captação de Serotonina , Paroxetina , Sertralina , PubMed , Fungos
11.
J. Health Biol. Sci. (Online) ; 10(1): 1-12, 01/jan./2022. tab, ilus
Artigo em Inglês | LILACS | ID: biblio-1378476

RESUMO

Objective: Analyze lysosomotropic agents and their action on COVID-19 targets using the molecular docking technique. Methods: Molecular docking analyses of these lysosomotropic agents were performed, namely of fluoxetine, imipramine, chloroquine, verapamil, tamoxifen, amitriptyline, and chlorpromazine against important targets for the pathogenesis of SARS-CoV-2. Results: The results revealed that the inhibitors bind to distinct regions of Mpro COVID-19, with variations in RMSD values from 1.325 to 1.962 Å and binding free energy of -5.2 to -4.3 kcal/mol. Furthermore, the analysis of the second target showed that all inhibitors bonded at the same site as the enzyme, and the interaction resulted in an RMSD variation of 0.735 to 1.562 Å and binding free energy ranging from -6.0 to -8.7 kcal/mol. Conclusion: Therefore, this study allows proposing the use of these lysosomotropic compounds. However, these computer simulations are just an initial step toward conceiving new projects for the development of antiviral molecules.


Objetivo: aAnalisar agentes lisossomotrópicos e sua ação em alvos de COVID-19 usando a técnica de docking molecular. Métodos: Foram realizadas análises de docagem molecular destes agentes lisossomotrópicos, nomeadamente de fluoxetina, imipramina, cloroquina, verapamil, tamoxifeno, amitriptilina e clorpromazina contra alvos importantes para a patogenia do SARS-CoV-2. Resultados: Os resultados revelaram que os inibidores se ligam a regiões distintas do Mpro COVID-19, com variações nos valores de RMSD de 1.325 a 1.962 Å e energia livre de ligação de -5,2 a -4,3 kcal/mol. Além disso, a análise do segundo alvo mostrou que todos os inibidores se ligaram no mesmo sítio da enzima, e a interação resultante em uma variação de RMSD de 0,735 a 1.562 Å e energia livre de ligação variando de -6,0 a -8,7 kcal/mol. Conclusão: Portanto, este estudo permite propor o uso desses compostos lisossomotrópicos. No entanto, essas simulações em computador são apenas um passo inicial para a concepção de novos projetos para o desenvolvimento de moléculas antivirais.


Assuntos
SARS-CoV-2 , COVID-19 , Antivirais , Cloroquina , Programas de Rastreamento , Fluoxetina , Amitriptilina , Imipramina
12.
J Clin Psychiatry ; 83(6)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36449476

RESUMO

Three drug dosing strategies can be employed to address dose-dependent drug adverse effects. The usual strategy is to continue the drug but at a lower dose; it would then take 5 half-lives of the drug for the new steady state to be attained and for a dose-dependent adverse effect to correspondingly attenuate. Such slow offset of the adverse effect could be disadvantageous for drugs such as fluoxetine, penfluridol, and cariprazine that have long half-lives. A second strategy is to stop the drug and to resume it at a lower dose when the adverse effect attenuates as the drug blood level falls. This strategy introduces subjectivity in timing the reintroduction of the drug, requires closer patient monitoring, and risks nonadherence and relapse. The third strategy is to stop the drug for a prespecified number of days and to then reintroduce it at a lower dose. From a knowledge of pharmacokinetics, it can be shown that stopping a drug for just 1 half-life and then resuming it at half the dose results in the immediate achievement of steady state; that is, there is no need to wait for 4 additional half-lives as with the usual strategy of dose reduction without dosing interruption. A limitation of this pharmacokinetically driven dosing strategy, however, is that it would work well in the average patient but not in those with outlying pharmacokinetic parameters.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Psicofarmacologia , Humanos , Meia-Vida , Fluoxetina , Retratamento
13.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36362409

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Ceramidas , COVID-19/tratamento farmacológico , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico
14.
Dev Psychobiol ; 64(8): e22345, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36426786

RESUMO

The antidepressant medication fluoxetine (FLX) is frequently prescribed for the management of mood-related illnesses in the adolescent population-yet its long-term neurobehavioral consequences are not understood. To investigate how juvenile FLX exposure influences feeding behavior in adulthood, we conducted two experiments. In Experiment 1, adolescent male and female Sprague-Dawley rats were administered with 20 mg/kg/day FLX (postnatal day [PND] 35-49) and exposed to a binge access paradigm in adulthood (PND72+) to evaluate potential alterations for sweetened-fat preference. No long-term FLX-induced differences in preference for sweetened fat versus chow, nor total caloric intake, were noted; however, females displayed higher preference for sweetened fat compared to males. In Experiment 2, PND35 male rats received FLX (PND35-49) and were exposed to chronic variable stress (CVS) in adulthood (PND74-88). During treatment, FLX decreased body weight and intake (meal size), but not total meal number. Also, no differences in meal pattern parameters were observed after FLX completion. Likewise, no differences in meal pattern parameters to a palatable diet (45% fat, 17% sucrose) presented from PND74 to PND88, even after CVS, were observed. Our findings indicate that juvenile FLX reduces body weight gain acutely via reduced meal size intake; however, no long-term changes in ad libitum feeding behavior or binge access to a palatable stimulus are evident.


Assuntos
Comportamento Alimentar , Fluoxetina , Ratos , Masculino , Feminino , Animais , Fluoxetina/farmacologia , Ratos Sprague-Dawley , Dieta , Peso Corporal
15.
Neurol India ; 70(5): 2125-2129, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36352620

RESUMO

Background: Severe peri-ictal respiratory dysfunction is a potential biomarker for high SUDEP risk and correlates with an attenuated hypercapnic ventilatory response (HCVR). Prior studies suggest a potential role for selective serotonergic reuptake inhibitors in modifying the HCVR, but this approach has not been studied in the epilepsy population. Objectives: To assess the feasibility of using fluoxetine to augment HCVR in epilepsy patients. Methods and Material: An inter-ictal HCVR was measured using a CO2 rebreathing technique in patients with epilepsy aged 18-75 years. Eligible participants were randomized to fluoxetine or placebo, and the HCVR was repeated at the end of week 4. Primary outcomes were recruitment and retention rate. Results: Of the 30 subjects enrolled, 22 were randomized (mean: 3.8 subjects/3 months), with a retention rate of 100% in fluoxetine and 95% in placebo. Conclusions: Our results demonstrate feasibility for a larger definitive future study to assess the efficacy of fluoxetine in augmenting HCVR.


Assuntos
Epilepsia , Fluoxetina , Humanos , Fluoxetina/uso terapêutico , Projetos Piloto , Dióxido de Carbono/fisiologia , Hipercapnia/tratamento farmacológico , Epilepsia/tratamento farmacológico
16.
Eur J Pharmacol ; 937: 175382, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36379258

RESUMO

Since a significant body of studies supports the involvement of glutamatergic neurotransmission in the neurobiology of obsessive-compulsive disorder (OCD). Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist with rapid and sustained antidepressant effect, raises as a potential new anti-OCD drug. Evidence from pre-clinical studies indicates that female mice are more sensitive than male mice to ketamine antidepressant effects. Our group previously showed that S-ketamine, one ketamine enantiomer, induces an acute anti-compulsive effect in male mice. Herein, we investigated this S-ketamine effect in female adult Swiss mice as monotherapy or as an adjuvant to fluoxetine, a selective serotonin reuptake inhibitor (SSRI), compared to male mice. For this purpose, we assessed the S-ketamine anti-compulsive-like effect in the marble-burying (MBT) and nest-building (NBT) tests in adult female Swiss mice. S-ketamine reduced the compulsive-like behaviour of female mice in both animal tests in a dose larger (30 mg/kg) than the effective dose in male Swiss mice (10 mg/kg, Tosta et al., 2019). The association of sub-effective doses of S-ketamine and fluoxetine effectively reduced the marble-burying behaviour of both male and female Swiss mice, although male mice present a better response. The variation of female sex hormones (oestrogen and progesterone), inferred by oestrous cycle and ovariectomy, did not influence S-ketamine's response. In conclusion, we found that female mice are less sensitive to S-ketamine's anti-compulsive-like effect than male mice as monotherapy or adjuvant treatment, but oscillations in female sex hormones concentrations do not seem to explain this difference.


Assuntos
Fluoxetina , Ketamina , Camundongos , Masculino , Feminino , Animais , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Ketamina/farmacologia , Ketamina/uso terapêutico , Antidepressivos/farmacologia , Antagonistas de Aminoácidos Excitatórios , Carbonato de Cálcio , Hormônios Esteroides Gonadais
17.
J Med Case Rep ; 16(1): 431, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36403006

RESUMO

BACKGROUND: Obsessive-compulsive disorder is a condition in which patients experience an obsession and/or a compulsion. It has a high impact on the quality of life, and is associated with an increased prevalence of psychiatric comorbidities in patients. Onychotillomania is an underestimated psychodermatosis caused by repeated self-inflicted damage to the nail unit. In patients, it is characterized by an obsessive or irrepressible impulse to repeatedly damage their own nails, resulting in their destruction. It is a chronic condition that is difficult to manage, largely because of its psychocutaneous character, as well as its high tendency to interact with underlying neuropsychiatric diseases or other behavioral disorders. Only a few studies have reported an association between obsessive-compulsive disorder and onychotillomania, which typically presents with therapeutic challenges. Cognitive behavioral therapy, physical-barrier approaches, and pharmaceutical treatments have been reported to be beneficial in the management of onychotillomania; however, no major clinical studies have investigated the effectiveness of these therapies. Onychotillomania remains a clinical and therapeutic issue owing to the lack of evidence-based treatment techniques. CASE PRESENTATION: We report a case of an 18-year-old, middle-eastern female patient who developed onychotillomania when she was being treated with paroxetine for obsessive-compulsive disorder and was showing partial improvement. The patient developed side effects from paroxetine, and was switched to fluoxetine. Thereafter, improvement in her obsessive-compulsive disorder was observed, which relapsed when treatment was discontinued. However, the onychotillomania symptoms did not reemerge. CONCLUSION: Onychotillomania typically presents both diagnostic and therapeutic challenges. Fluoxetine plays an important role in the treatment of onychotillomania and other psychiatric disorders. However, large-scale studies should be conducted before these outcomes can be generalized.


Assuntos
Fluoxetina , Transtorno Obsessivo-Compulsivo , Humanos , Feminino , Adolescente , Fluoxetina/uso terapêutico , Paroxetina/uso terapêutico , Qualidade de Vida , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Preparações Farmacêuticas
18.
Cochrane Database Syst Rev ; 10: CD013337, 2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36190739

RESUMO

BACKGROUND: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem. OBJECTIVES: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia. SEARCH METHODS: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI. MAIN RESULTS: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence. AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.


Assuntos
Antipsicóticos , Melatonina , Metformina , Esquizofrenia , Antipsicóticos/efeitos adversos , beta-Histina/uso terapêutico , Famotidina/uso terapêutico , Fluoxetina/uso terapêutico , Humanos , Melatonina/uso terapêutico , Metformina/uso terapêutico , Náusea/tratamento farmacológico , Nizatidina/uso terapêutico , Ranitidina/uso terapêutico , Reboxetina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controle , Topiramato/uso terapêutico , Aumento de Peso
19.
Environ Sci Technol ; 56(22): 15848-15859, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36260920

RESUMO

The ubiquitous presence of fluoxetine (FLX) in aquatic environments poses great threat to fish species. However, little is known about its deleterious impacts on fish olfaction. In this study, the olfactory toxicity of FLX at environmentally realistic levels was assessed by monitoring the behavioral and electroolfactogram (EOG) responses to olfactory stimuli with goldfish (Carassius auratus), and the toxification mechanisms underlying the observed olfaction dysfunction were also investigated. Our results showed that the behavioral and EOG responses of goldfish to olfactory stimuli were significantly weakened by FLX, indicating an evident toxicity of FLX to olfaction. Moreover, FLX exposure led to significant alterations in olfactory initiation-related genes, suppression of ion pumps (Ca2+-ATPase and Na+/K+-ATPase), tissue lesions, and fewer olfactory sensory neurons in olfactory epithelium. In addition to altering the expression of olfactory transmission-related genes, comparative metabolomic analysis found that olfaction-related neurotransmitters (i.e., l-glutamate and acetylcholine) and the olfactory transduction pathway were significantly affected by FLX. Furthermore, evident tissue lesions, aggravated lipid peroxidation and apoptosis, and less neuropeptide Y were observed in the olfactory bulbs of FLX-exposed goldfish. Our findings indicate that FLX may hamper goldfish olfaction by interfering with the initiation, transmission, and processing of olfactory signals.


Assuntos
Fluoxetina , Carpa Dourada , Animais , Carpa Dourada/genética , Olfato , Adenosina Trifosfatases
20.
Pharm Biol ; 60(1): 1850-1864, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205539

RESUMO

CONTEXT: Lily bulb and Rehmannia decoction (LBRD), consisting of Lilium henryi Baker (Liliaceae) and Rehmannia glutinosa (Gaertn) DC (Plantaginaceae), is a specialized traditional Chinese medicine formula for treating depression. However, the underlying mechanisms, especially the relationship between LBRD efficacy and metabolomics, remains unclear. OBJECTIVE: This study was aimed to investigate the metabolic mechanism of LBRD in treating depression. MATERIALS AND METHODS: Network pharmacology was conducted using SwissTargetPrediction, DisGeNET, DrugBank, Metascape, etc., to construct component-target-pathway networks. The depression-like model was induced by intraperitoneal injection with lipopolysaccharide (LPS) (0.3 mg/kg) for 14 consecutive days. After the administration of LBRD (90 g/kg) and fluoxetine (2 mg/kg) for 14 days, we assessed behaviour and the levels of neurotransmitter, inflammatory cytokine and circulating stress hormone. Prefrontal metabolites of rats were detected by using liquid chromatography-mass spectrometry metabolomics method. RESULTS: The results of network pharmacology showed that LBRD mainly acted on neurotransmitter and second messenger pathways. Compared to the model group, LBRD significantly ameliorated depressive phenotypes and increased the level of 5-HT (13.4%) and GABA (24.8%), as well as decreased IL-1ß (30.7%), IL-6 (32.8%) and TNF-α (26.6%). Followed by LBRD treatment, the main metabolites in prefrontal tissue were contributed to retrograde endocannabinoid signalling, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, autophagy signal pathway, etc. DISCUSSION AND CONCLUSIONS: LBRD were effective at increasing neurotransmitter, attenuating proinflammatory cytokine and regulating glycerophospholipid metabolism and glutamatergic synapse, thereby ameliorating depressive phenotypes. This research will offer reference for elucidating the metabolomic mechanism underlying novel antidepressant agents contained LBRD formula.


Assuntos
Medicamentos de Ervas Chinesas , Lilium , Rehmannia , Animais , Antidepressivos/farmacologia , Citocinas , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Endocanabinoides , Fluoxetina , Glicosilfosfatidilinositóis , Hormônios , Interleucina-6 , Lipopolissacarídeos/toxicidade , Metabolômica/métodos , Farmacologia em Rede , Extratos Vegetais , Ratos , Serotonina , Fator de Necrose Tumoral alfa , Ácido gama-Aminobutírico
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