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1.
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
2.
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
3.
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
4.
Emerg Microbes Infect ; 9(1): 2245-2255, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32975484

RESUMO

The Coronavirus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19 severity. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibited the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects and also exerted potent antiviral activity against two currently circulating influenza A virus subtypes, an effect which was also observed upon treatment with the FIASMAs amiodarone and imipramine. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract enveloped viruses, including SARS-CoV-2.


Assuntos
Antidepressivos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Inibidores Enzimáticos/farmacologia , Fluoxetina/farmacologia , Pneumonia Viral/virologia , Betacoronavirus/fisiologia , Linhagem Celular , Endossomos/virologia , Humanos , Pandemias , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
5.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
6.
Psychopharmacology (Berl) ; 237(8): 2555-2568, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32533210

RESUMO

RATIONALE: Selective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown. OBJECTIVE: Our aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms. RESULTS: Perinatal FLX exposure shortened the free-running tau in response to the 5-HT1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT1A receptor sensitivity. No differences were found in 5-HT1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression. CONCLUSIONS: Perinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Fluoxetina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Adaptação Psicológica/fisiologia , Animais , Antidepressivos/farmacologia , Ritmo Circadiano/fisiologia , Feminino , Ratos , Ratos Transgênicos , Ratos Wistar , Serotonina/metabolismo , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/fisiologia
7.
J Pharmacol Exp Ther ; 374(1): 84-92, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32332112

RESUMO

Urinary incontinence is defined as an involuntary leakage of urine and is categorized into three types: stress urinary incontinence (SUI), urge urinary incontinence (UUI), and mixed urinary incontinence, which includes symptoms of SUI and UUI. As the underlying mechanisms of SUI and UUI are different, no drug is approved to treat all three types of urinary incontinence. TAS-303 is a selective norepinephrine reuptake inhibitor and has therapeutic potential for patients with SUI. In this report, we describe newly discovered pharmacological properties of TAS-303 and its effects on bladder function. Radioligand binding studies showed that TAS-303 inhibits M3 muscarinic receptor binding, with a Ki value of 547 nM. TAS-303 at 1, 3, and 10 mg/kg dose-dependently prolonged the intercontraction interval of carbachol-induced detrusor overactivity in rats, exhibiting a maximal effect that was comparable to tolterodine. These effects may result from coordinated regulation of bladder afferent activity via M3 muscarinic inhibition and ß3 adrenoreceptor activation by norepinephrine elevation due to norepinephrine transporter inhibition. Moreover, TAS-303 at the effective dose for bladder function did not induce dry mouth or constipation in rats, showing that this compound may have a lower risk of antimuscarinic side effects. Thus, TAS-303 is expected to be a new profile agent with therapeutic potential for all types of urinary incontinence. SIGNIFICANCE STATEMENT: Urinary incontinence is categorized into stress, urge, and mixed urinary incontinence, but because the underlying mechanisms of each differ, no drugs are available that treat all three. TAS-303 has therapeutic potential for stress urinary incontinence. This study describes newly discovered pharmacological properties of TAS-303, which ameliorated bladder afferent activity partly via M3 muscarinic inhibition, indicating improvement in urge urinary incontinence, and highlights the potential of TAS-303 as a new therapeutic agent for all types of urinary incontinence.


Assuntos
Carbacol/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Atropina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Contração Muscular/efeitos dos fármacos , Ratos , Receptores Muscarínicos/metabolismo , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/metabolismo
8.
Biomed Res Int ; 2020: 2794263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185198

RESUMO

Background: Fluoxetine (FLU) is the first-line and widely used medication for depression; however, FLU treatment is almost ineffective in 30%-40% of patients with depression. In addition, there are some problems in FLU treatment, such as delayed efficacy, large side effects, and poor tolerance. Chaihu Shugan San (CSS) is a classic and effective antidepressant Chinese herbal medicine that has been used in China for thousands of years. CSS or coadministration of CSS and FLU has become one of the most recommended methods in the treatment of depression in China. However, the specific pathways of CSS and coadministration of CSS and FLU for antidepressant are still unclear. Objective: This study was designed to evaluate the antidepressant effects of CSS and coadministration of CSS and FLU. Methods: The chronic unpredictable mild stress (CUMS) rat model was used to simulate depression. 120 healthy adult male Sprague-Dawley (SD) rats were randomly divided into seven groups: the control group, CUMS group, low-dose CSS group, high-dose CSS group, FLU group, coadministration of low-dose CSS and FLU group, and coadministration of high-dose CSS and FLU group. The rats in different groups were given different interventions. Then, the depression-like behavior and cognitive function were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and Y-maze test. What is more, the antidepressant mechanism of CSS and coadministration of CSS and FLU were studied through BDNF mRNA, ERK mRNA, CREB mRNA, BDNF, p-ERK/ERK, and p-CREB/CREB levels in the hippocampus and frontal cortex by Western blot and RT-PCR. Results: Compared with the CUMS group, CSS and coadministration of CSS and FLU could alleviate the depressive symptoms and improve cognitive function in CUMS rats (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (Discussion and Conclusion. Finally, we found that both CSS and coadministration of CSS and FLU play an antidepressant role, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway in the hippocampus and frontal cortex. Among them, the coadministration of CSS and FLU can enhance the antidepressant effect of CSS or FLU alone, and the underlying mechanism needs further investigation.


Assuntos
Antidepressivos/farmacologia , Fluoxetina/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Nootrópicos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo
9.
J Neurol Neurosurg Psychiatry ; 91(5): 526-532, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32165373

RESUMO

OBJECTIVE: Direct inhibition of acetylcholine receptor (AChR) function by autoantibodies (Abs) is considered a rare pathogenic mechanism in myasthenia gravis (MG), but is usually studied on AChRs expressed in cell lines, rather than tightly clustered by the intracellular scaffolding protein, rapsyn, as at the intact neuromuscular junction. We hypothesised that clustered AChRs would provide a better target for investigating the functional effects of AChR-Abs. METHODS: Acetylcholine-induced currents were measured using whole-cell patch clamping and a fast perfusion system to assess fast (<2 min) functional effects of the serum samples. The sensitivity, specificity and rapidity of the system were first demonstrated by applying maternal AChR-Ab positive plasmas known to inhibit fetal AChR function in TE671 cells. Eleven previously untested AChR-Ab positive MG sera, 10 AChR-Ab negative MG sera and 5 healthy control sera were then applied to unclustered and rapsyn-clustered human adult AChRs in CN21 cells. RESULTS: The maternal AChR-Ab positive plasmas reduced fetal AChR currents, but not adult AChR currents, by >80% within 100 s. Only 2/11 AChR-Ab positive sera inhibited AChR currents in unclustered AChRs, but 6/11 AChR-Ab positive sera compared with none of the 10 AChR-Ab negative sera (p=0.0020) inhibited rapsyn-clustered AChR currents, and current inhibition by the AChR-Ab positive sera was greater when the AChRs were clustered (p=0.0385). None of the sera had detectable effects on desensitisation or recovery from desensitisation. CONCLUSION: These results show that antibodies can inhibit AChR function rapidly and demonstrate the importance of clustering in exploring pathogenic disease mechanisms of MG Abs.


Assuntos
Autoanticorpos/imunologia , Proteínas Musculares/imunologia , Miastenia Gravis/imunologia , Receptores Colinérgicos/imunologia , Adolescente , Adulto , Idoso , Bungarotoxinas/farmacologia , Linhagem Celular , Fenômenos Eletrofisiológicos , Feminino , Fluoxetina/farmacologia , Humanos , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Miastenia Gravis/etiologia , Técnicas de Patch-Clamp , Receptores Colinérgicos/efeitos dos fármacos , Adulto Jovem
10.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188355, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135169

RESUMO

The human ether-à-go-go related gene (HERG) encodes the alpha subunit of Kv11.1, which is a voltage-gated K+ channel protein mainly expressed in heart and brain tissue. HERG plays critical role in cardiac repolarization, and mutations in HERG can cause long QT syndrome. More recently, evidence has emerged that HERG channels are aberrantly expressed in many kinds of cancer cells and play important roles in cancer progression. HERG could therefore be a potential biomarker for cancer and a possible molecular target for anticancer drug design. HERG affects a number of cellular processes, including cell proliferation, apoptosis, angiogenesis and migration, any of which could be affected by dysregulation of HERG. This review provides an overview of available information on HERG channel as it relates to cancer, with focus on the mechanism by which HERG influences cancer progression. Molecular docking attempts suggest two possible protein-protein interactions of HERG with the ß1-integrin receptor and the transcription factor STAT-1 as novel HERG-directed therapeutic targeting which avoids possible cardiotoxicity. The role of epigenetics in regulating HERG channel expression and activity in cancer will also be discussed. Finally, given its inherent extracellular accessibility as an ion channel, we discuss regulatory roles of this molecule in cancer physiology and therapeutic potential. Future research should be directed to explore the possibilities of therapeutic interventions targeting HERG channels while minding possible complications.


Assuntos
Carcinogênese/patologia , Canal de Potássio ERG1/metabolismo , Integrina beta1/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Carcinogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/química , Canal de Potássio ERG1/genética , Epigênese Genética/efeitos dos fármacos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Síndrome do QT Longo/genética , Potenciais da Membrana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação , Miócitos Cardíacos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Conformação Proteica em alfa-Hélice , Mapeamento de Interação de Proteínas , Estrutura Quaternária de Proteína , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfanilamidas/farmacologia , Sulfanilamidas/uso terapêutico
11.
Biochem Pharmacol ; 175: 113864, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088265

RESUMO

Interleukin (IL)-1 signaling leads to production of pro-inflammatory mediators and is regulated by receptor endocytosis. Lysosomotropic drugs have been linked to increased pro-inflammatory responses under sterile inflammatory conditions but the underlying mechanisms have not been fully elucidated. Here, we report that lysosomotropic drugs potentiate pro-inflammatory effects in response to IL-1ß via a mechanism involving reactive oxygen species, p38 mitogen-activated protein kinase and reduced IL-1 receptor internalization. Chloroquine and hydroxychloroquine increased IL-1ß-induced CXCL8 secretion in macrophages which was critically dependent on the lysosomotropic character and inhibition of macroautophagy but independent from the NLRP3 inflammasome. Co-stimulation with the autophagy inducer interferon gamma attenuated CXCL8 release. Other lysosomotropic drugs like bafilomycin A1, fluoxetine and chlorpromazine but also the endocytosis inhibitor dynasore showed similar pro-inflammatory responses. Increased cell surface expression of IL-1 receptor suggests reduced receptor degradation in the presence of lysosomotropic drugs. Our findings provide new insights into a potentially crucial immunoregulatory mechanism in macrophages that may explain how lysosomotropic drugs drive sterile inflammation.


Assuntos
Autofagia/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lisossomos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptores de Interleucina-1/antagonistas & inibidores , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Clorpromazina/farmacologia , Endocitose/efeitos dos fármacos , Fluoxetina/farmacologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Lisossomos/imunologia , Macrófagos/imunologia , Transdução de Sinais , Células THP-1
12.
Pharmacol Rep ; 72(2): 340-349, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109308

RESUMO

BACKGROUND: Fluoxetine is one of the most widely prescribed antidepressants and a selective inhibitor of presynaptic 5-HT transporters. The fornix is the commissural and projection fiber that transmits signals from the hippocampus to other parts of the brain and opposite site of hippocampus. The corpus callosum (CC) is the largest of the commissural fibers that link the cerebral cortex of the left and right cerebral hemispheres. These brain regions play pivotal roles in cognitive functions, and functional abnormalities in these regions have been implicated in the development of various brain diseases. The purpose of the present study was to investigate the effects of fluoxetine on the proliferation and/or survival of microglia and oligodendrocyte progenitor cells (OPCs) in the fornix and CC, the white matter connecting cortical-limbic system, of the adult mouse brain. METHODS: The effects of fluoxetine on the proliferation and/or survival of microglia and OPCs were examined in lipopolysaccharide (LPS)-treated and normal mice. Proliferating cells were detected in mice that drank water containing the thymidine analog, bromodeoxyuridine (BrdU), using immunohistochemistry. RESULT: Fluoxetine significantly attenuated LPS-induced increases in the number of BrdU-labeled microglia and morphological activation from the ramified to ameboid shape, and decreased the number of BrdU-labeled OPCs under basal conditions. CONCLUSIONS: The present results indicate that fluoxetine exerts inhibitory effects on LPS-induced increases in the proliferation and/or survival and morphological activation of microglia and basal proliferation and/or survival of OPCs in the fornix and CC of adult mice.


Assuntos
Proliferação de Células/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Fluoxetina/farmacologia , Fórnice/efeitos dos fármacos , Microglia/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Corpo Caloso/patologia , Relação Dose-Resposta a Droga , Fórnice/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos ICR , Microglia/patologia , Microscopia Confocal , Células Precursoras de Oligodendrócitos/patologia
13.
Psychopharmacology (Berl) ; 237(5): 1281-1290, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31965254

RESUMO

RATIONALE: Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-associated behaviors and increase adult hippocampal neurogenesis in male rodents. OBJECTIVE: Very few studies have looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents. METHODS: Here, we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle. RESULTS: In naturally cycling C57BL/6J females, fluoxetine decreases negative valence behaviors associated with anxiety in the elevated plus maze and novelty-suppressed feeding task, reduces immobility time in forced swim test, and increases adult hippocampal neurogenesis. Interestingly, the effects of fluoxetine on several negative valence behavior and adult hippocampal neurogenesis measures were mainly found within the estrus and diestrus phases of the estrous cycle. CONCLUSIONS: Taken together, these data are the first to illustrate the effects of fluoxetine on behavior and adult hippocampal neurogenesis across all four phases of the murine estrous cycle.


Assuntos
Ciclo Estral/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/psicologia , Ciclo Estral/fisiologia , Feminino , Fluoxetina/uso terapêutico , Hipocampo/citologia , Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Inibidores de Captação de Serotonina/uso terapêutico
14.
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
15.
Adv Mater ; 32(2): e1906050, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777995

RESUMO

A black phosphorus (BP)-nanosheet-based drug-delivery system containing a therapeutic drug (Fluoxetine, Flu) is synthesized. According to subsequent behavioral, biochemical, and electrophysiological analysis, BP-Flu, after irradiated with near-infrared light (808 nm), can significantly reduce the therapy time of depression. Meanwhile, the inherent biotoxicity of Flu is also alleviated.


Assuntos
Depressão/tratamento farmacológico , Portadores de Fármacos/química , Fluoxetina/química , Fluoxetina/farmacologia , Fósforo/química , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/metabolismo , Depressão/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fluoxetina/uso terapêutico , Fluoxetina/toxicidade , Cinética , Camundongos
16.
Am J Physiol Renal Physiol ; 318(2): F354-F362, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869244

RESUMO

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1ß. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.


Assuntos
Afeto , Comportamento Animal , Ciclofosfamida , Cistite/induzido quimicamente , Depressão/etiologia , Encefalite/etiologia , Hipocampo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Afeto/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Caspase 1/metabolismo , Cistite/metabolismo , Cistite/fisiopatologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Fluoxetina/farmacologia , Glibureto/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Mesna/farmacologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos Sprague-Dawley , Transdução de Sinais
17.
J Affect Disord ; 260: 302-313, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521867

RESUMO

BACKGROUND: Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated. METHOD: C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg-1), SDS + FLUOX (3 mg kg-1), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons. RESULT: The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CA1 pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB). CONCLUSION: Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression.


Assuntos
Acetilação/efeitos dos fármacos , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Modelos Animais de Doenças , Fluoxetina/farmacologia , Hipocampo/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/tratamento farmacológico , Natação
18.
Psychopharmacology (Berl) ; 237(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473777

RESUMO

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


Assuntos
Fluoxetina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo
19.
Synapse ; 74(1): e22130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31449695

RESUMO

Due to the prevalence of depression in women, female rats may be a better models for antidepressant research than males. In male rats, fluoxetine inhibited the serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) which is reducing the immobility time in the repeated forced swimming test (rFST). The performance of female rats in this test is unknown. In this study, responses of male and female rats in the rFST under chronic treatment with fluoxetine and the function of SERT in their brains were examined. Wistar rats received oral fluoxetine (females: 0, 1, 2.5, or 5 mg kg-1  day-1 ; males: 0 or 2.5 mg kg-1  day-1 ; in sucrose 10%, 1.5 ml/rat) 1 hr before the test daily for 12 days over the course of the rFST. rFST consisted of a 15 min pretest followed by 5 min sessions of swimming at 1 (test), 7 (retest 1), and 14 (retest 2) days later. SERT functioning was assessed by ex vivo assays of the frontal cortex and hippocampus of rats. Fluoxetine reduced immobility time of males in the rFST while it failed to do so in females. In vitro treatment with fluoxetine inhibited the uptake of 5-HT of both sexes similarly, while in vivo chronic administration of fluoxetine failed to do so. In summary, rats responded to the chronic treatment with fluoxetine in a sexually dimorphic fashion during the rFST despite the functioning of SERT in their brains remaining equally unchanged. Hence, our data suggest that sexually dimorphic responses to fluoxetine in rFST may be unrelated to the function of SERT in rat brains.


Assuntos
Fluoxetina/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Fatores Sexuais , Natação
20.
Appl Physiol Nutr Metab ; 45(1): 24-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31084576

RESUMO

The present study designed and evaluated a polyherbal premix comprising Macrotyloma uniflorum, whey protein, Zingiber officinale, and Mentha piperita. Animals were fed a high-fat diet (HFD) for 30 days and were daily administered the premix (1.5 g/kg) in milk (PM) and water (PW), aerobic exercise (AE), premix in milk and water along with AE (PMAE and PWAE), ferulic acid (100 mg/kg), and the reference drug fluoxetine (6 mg/kg). All treatments showed significant reduction in food intake, weight gain, abdominal circumference, and body mass index compared with their initial values. All treatments generated a faster peak of the satiety marker cholecystokinin compared with the HFD group and control groups; PMAE and PWAE exhibited sustained satiety. The HFD-elevated blood glucose levels were significantly attenuated on the 30th day by all treatments when compared with their 15th day and basal values; PMAE exhibited the best results. All treatments significantly attenuated the HFD-elevated serum insulin, homeostasis model assessment of insulin resistance, C-reactive protein, triglycerides, total cholesterol, very-low-density lipoprotein, and low-density lipoprotein levels and significantly restored the HFD-depleted high-density lipoprotein and adiponectin levels. HFD-elevated thiobarbituric acid reactive substances values were attenuated successfully and the HFD-depleted reduced glutathione, superoxide dismutase, and catalase levels were significantly restored by all treatments. The histological findings corroborated the biochemical results. Novelty The polyherbal premix brought about appetite regulation and induction of satiety to control obesity in HFD-fed rats through homeostasis of energy metabolism. The premix along with exercise is a complete way to combat obesity.


Assuntos
Fármacos Antiobesidade/farmacologia , Fabaceae , Gengibre , Obesidade/metabolismo , Preparações de Plantas/farmacologia , Tecido Adiposo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Colecistocinina/sangue , Ácidos Cumáricos/farmacologia , Dieta Hiperlipídica , Feminino , Fluoxetina/farmacologia , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Sprague-Dawley , Resposta de Saciedade/efeitos dos fármacos , Soro do Leite , Proteínas do Soro do Leite/farmacologia
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