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1.
BMC Psychiatry ; 22(1): 590, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064335

RESUMO

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.


Assuntos
Fluoxetina , Lipopolissacarídeos , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Hipocampo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Inflamação/metabolismo , Privação Materna , Camundongos , Sistema Hipófise-Suprarrenal/metabolismo , Serotonina/metabolismo
2.
Basic Res Cardiol ; 117(1): 43, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36038749

RESUMO

Antidepressants have been reported to enhance stroke recovery independent of the presence of depressive symptoms. They have recently been proposed to exert their mood-stabilizing actions by inhibition of acid sphingomyelinase (ASM), which catalyzes the hydrolysis of sphingomyelin to ceramide. Their restorative action post-ischemia/reperfusion (I/R) still had to be defined. Mice subjected to middle cerebral artery occlusion or cerebral microvascular endothelial cells exposed to oxygen-glucose deprivation were treated with vehicle or with the chemically and pharmacologically distinct antidepressants amitriptyline, fluoxetine or desipramine. Brain ASM activity significantly increased post-I/R, in line with elevated ceramide levels in microvessels. ASM inhibition by amitriptyline reduced ceramide levels, and increased microvascular length and branching point density in wildtype, but not sphingomyelinase phosphodiesterase-1 ([Smpd1]-/-) (i.e., ASM-deficient) mice, as assessed by 3D light sheet microscopy. In cell culture, amitriptyline, fluoxetine, and desipramine increased endothelial tube formation, migration, VEGFR2 abundance and VEGF release. This effect was abolished by Smpd1 knockdown. Mechanistically, the promotion of angiogenesis by ASM inhibitors was mediated by small extracellular vesicles (sEVs) released from endothelial cells, which exhibited enhanced uptake in target cells. Proteomic analysis of sEVs revealed that ASM deactivation differentially regulated proteins implicated in protein export, focal adhesion, and extracellular matrix interaction. In vivo, the increased angiogenesis was accompanied by a profound brain remodeling response with increased blood-brain barrier integrity, reduced leukocyte infiltrates and increased neuronal survival. Antidepressive drugs potently boost angiogenesis in an ASM-dependent way. The release of sEVs by ASM inhibitors disclosed an elegant target, via which brain remodeling post-I/R can be amplified.


Assuntos
Amitriptilina , Vesículas Extracelulares , Amitriptilina/metabolismo , Amitriptilina/farmacologia , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Encéfalo/metabolismo , Ceramidas/metabolismo , Ceramidas/farmacologia , Desipramina/metabolismo , Desipramina/farmacologia , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Fluoxetina/metabolismo , Fluoxetina/farmacologia , Isquemia/metabolismo , Camundongos , Proteômica
3.
Neurosci Lett ; 787: 136818, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35931277

RESUMO

In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.


Assuntos
Experiências Adversas da Infância , Fluoxetina , Animais , Aprendizagem da Esquiva , Peso Corporal , Fluoxetina/farmacologia , Cloreto de Lítio/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Sacarina , Paladar
4.
Transl Psychiatry ; 12(1): 339, 2022 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-35987907

RESUMO

Depression is one of the most prevalent mental disorders associated with reductions in bone mineral density and increased fracture risk. Fluoxetine is a highly prescribed selective serotonin reuptake inhibitor (SSRI) in the treatment of depression and is reported to be a risk factor for fractures. The present study examined the effect of fluoxetine on bone microarchitecture and the mechanical properties under chronic mild stress (CMS), a rodent model of depression. Thirty-one 6-9 week-old rats were allocated to 4 groups: 1) CMS + fluoxetine group (n = 10), 2) fluoxetine-only group (n = 5), 3) CMS + placebo group (n = 10) and 4) control group (no CMS and treatment) (n = 6). After 16 weeks, bone microarchitecture of the distal femur was analyzed by µCT. Mechanical properties were assessed by the three-point bending test, and antidepressant efficacy was determined by sucrose preference and forced swimming tests. Significant correlations were found between volume of sucrose intake and bone volume/tissue volume (BV/TV) (p = 0.019) and elastic absorption energy (p = 0.001) in the fluoxetine only group. The fluoxetine-only group showed significantly higher in the second moment of area in y-direction (p = 0.0298), horizontal outer diameter (mm) (p = 0.0488) and average midshaft thickness (mm) (p = 0.00047) than control group. Comparing with the control group, there was a significant reduction in trabecular number (Tb.N) in the CMS + fluoxetine group (p = 0.026) but not the fluoxetine-only group (p > 0.05). Significant increases in trabecular separation were observed in the metaphysis of CMS + placebo (p = 0.003) and CMS + fluoxetine (p = 0.004) groups when compared to the control group but not in the fluoxetine-only group (p > 0.05). During the three-point bending test, the fluoxetine-only group demonstrated significantly higher structural strength than controls (p = 0.04). Micro computed tomography (µCT) slices showed loss of trabecular bone in the metaphysis region of the CMS + fluoxetine and CMS + placebo groups but not the fluoxetine-only and control groups. In an animal model of depression, the adverse effect on the bone microarchitecture was caused by CMS but not by fluoxetine. Without exposure to CMS, fluoxetine significantly increased the cross-sectional area, trabecular bone area, structural strength and osteoblasts / bone area as compared to control condition.


Assuntos
Depressão , Fluoxetina , Animais , Densidade Óssea , Depressão/diagnóstico por imagem , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Ratos , Roedores , Sacarose , Microtomografia por Raio-X
5.
Emerg Microbes Infect ; 11(1): 2160-2175, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36000328

RESUMO

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.


Assuntos
COVID-19 , Vírus da Influenza A , Influenza Humana , Animais , Antivirais/farmacologia , Fluoxetina/farmacologia , Humanos , Vírus da Influenza A/fisiologia , Influenza Humana/tratamento farmacológico , Interferons , Pulmão , Camundongos , SARS-CoV-2 , Replicação Viral
6.
Behav Brain Res ; 433: 114004, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35811001

RESUMO

Post-traumatic stress disorder is a major public health problem due to its frequency, chronicity, and disability that impact daily life. Studies have evidenced that the activation/inhibition of autophagy and excessive activation of microglia have a relationship with PTSD. For this purpose, C57BL/6 mice were employed to establish the post-traumatic stress disorder pathology mice model by conditioned fear and single prolonged stress (CF + SPS). Fluoxetine and PLX3397 were administered. PTSD-like behaviors were alleviated following fluoxetine treatment, evidenced via open field and conditioned fear test. Autophagy-associated proteins were upregulated, and inflammation factors were reduced after fluoxetine treatment. Microglia depletion mice showed a lower inflammatory level. In conclusion, fluoxetine can promote autophagy and inhibit neuroinflammation in mice model of PTSD, providing a theoretical basis for fluoxetine in treating PTSD.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Animais , Autofagia , Modelos Animais de Doenças , Fluoxetina/farmacologia , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico
7.
Anticancer Res ; 42(8): 3807-3814, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35896246

RESUMO

BACKGROUND/AIM: Breast cancer (BC) is the most common cancer and second leading cause of death in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive type of BC, while the treatment option is limited and has long been considered as a major unmet need. Meta-analysis indicated the anti-tumor potential of anti-depressants, especially selective serotonin-reuptake inhibitors (SSRIs). The SSRI fluoxetine has been shown to suppress BC and ovarian cancer cell growth; however, whether it suppresses tumor progression in vivo is unclear. MATERIALS AND METHODS: We established an 4T1 bearing animal model, an orthotopic TNBC model, to identify the mechanism and therapeutic efficacy of fluoxetine. RESULTS: Tumor growth evaluated by caliper and computed tomography scan demonstrated the inhibition effect by fluoxetine treatment. Immunohistochemistry showed that the expression of STAT3-mediated epithelial-to-mesenchymal transition (EMT) proteins and apoptosis-related proteins was decreased. CONCLUSION: Fluoxetine may induce an anti-TNBC effect via inactivating STAT3 signaling transduction and triggering the caspase-mediated apoptotic pathway.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Fluoxetina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
8.
Neurosci Lett ; 785: 136787, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35820551

RESUMO

The NLRP3-mediated pyroptosis, which could affect inflammation response, plays a key role in the development of depression. Acupuncture has been shown to be an effective treatment for depression. In this study, we aimed to determine whether acupuncture could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by reducing inflammation. Here, depression model of rats was induced by chronic unpredictable mild stress (CUMS) for 4 weeks. Acupuncture group was subjected to acupuncture at the Shangxing (GV23) and Fengfu (GV16) acupoints for 20 min every other day (a total of 14 times). Fluoxetine group was administered with fluoxetine (2.1 mg/kg with the concentration of 0.21 mg/mL) by oral gavage (1 mL/100 g) once a day for 28 days. Rats' depression-like phenotypes were reflected with behavioral tests and biological detection methods. Results showed that acupuncture significantly improved the depression-like behavior of CUMS rat, suppressed the expressions of NLRP3, ASC, caspase-1, GSDMD, IL-1ß, IL-18, HMGB1, IFN-γ, IL-6 and TNF-α in the serum and hippocampus, restored the %area of microglia, astrocytes and neuronal cells in the hippocampus. These indicate that acupuncture can prevent CUMS-induced depression-like behaviors by reducing NLRP3-mediated pyroptosis and inflammation.


Assuntos
Terapia por Acupuntura , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Depressão/metabolismo , Depressão/terapia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Inflamassomos/metabolismo , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/terapia
9.
Eur J Drug Metab Pharmacokinet ; 47(5): 741-747, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35838883

RESUMO

BACKGROUND AND OBJECTIVES: Herein, hydroxylation activities at the 6ß-position and 21-position of progesterone mediated by human cytochrome P450 (CYP) 2D6 and its variants and the effects of psychotropic drugs on these hydroxylation activities were compared to clarify whether CYP2D6 polymorphisms and psychotropic drugs impact neurosteroid levels in the brain. METHODS: Progesterone was incubated with CYP2D6.1, CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr) in the absence or presence of typical psychotropic drugs (fluvoxamine, fluoxetine, paroxetine, fluphenazine, and milnacipran) and endogenous steroids (testosterone and cortisol). Then, 6ß- and 21-hydroxyprogesterone levels were determined by high-performance liquid chromatography. RESULTS: Although the Michaelis-Menten constants (Km) for progesterone 6ß- and 21-hydroxylation reactions mediated by the different CYP2D6 variants were similar, the maximal velocity (Vmax) values of the reactions mediated by CYP2D6.1 and CYP2D6.2 were the highest, followed by those mediated by CYP2D6.39 and CYP2D6.10. Thus, the of progesterone 6ß- and/or 21-hydroxylation reactions mediated by CYP2D6.1 and CYP2D6.2 showed the highest Vmax/Km values, followed by the reactions mediated by CYP2D6.39. All investigated compounds inhibited progesterone 21-hydroxylation mediated by CYP2D6 variants at high concentrations. Interestingly, at low concentrations, fluoxetine increased progesterone 21-hydroxylation mediated by CYP2D6.1, but not that mediated by CYP2D6.2 or CYP2D6.10. In addition, the Km value for CYP2D6.2 was elevated in the presence of fluoxetine, whereas the value for CYP2D6.1 was unaltered; however, Vmax values of both CYP2D6.1 and CYP2D6.2 were increased. Paroxetine competitively inhibited CYP2D6.1- and CYP2D6.2-mediated progesterone 21-hydroxylation. CONCLUSIONS: These results suggest that CYP2D6 polymorphism can affect the stimulation/inhibition of progesterone 21-hydroxylation.


Assuntos
Citocromo P-450 CYP2D6 , Progesterona , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Fluoxetina/farmacologia , Humanos , Hidroxilação , Paroxetina/farmacologia , Progesterona/química , Psicotrópicos
10.
Biomed Pharmacother ; 153: 113268, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35777221

RESUMO

Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), increases the serotonin levels in the brain to treat depression. Antidepressants have been demonstrated to modulate circadian rhythm, but the underlying mechanisms by which antidepressants regulate circadian rhythm require more research. This study aimed to investigate the role of FLX on circadian rhythm by analyzing the movement behavior and internal circadian oscillations in zebrafish. The results showed that the expression of clock genes clock1a and bmal1b was significantly down-regulated, and the amplitude reduction and phase shift were observed after FLX treatment. Furthermore, FLX exposure inhibited the expression of aanat2, which led to a decrease in nocturnal melatonin secretion. aanat2-/- larvae showed disrupted circadian rhythm. These findings may help reveal the effect of FLX exposure on the circadian rhythm and locomotor activity. It may provide theoretical data for the clinical application of FLX.


Assuntos
Fluoxetina , Melatonina , Animais , Antidepressivos/farmacologia , Ritmo Circadiano/genética , Fluoxetina/farmacologia , Melatonina/metabolismo , Melatonina/farmacologia , Peixe-Zebra/metabolismo
11.
Prog Neurobiol ; 217: 102333, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35872219

RESUMO

The neurotrophin brain-derived neurotrophic factor (BDNF) stimulates adult neurogenesis, but also influences structural plasticity and function of serotonergic neurons. Both, BDNF/TrkB signaling and the serotonergic system modulate behavioral responses to stress and can lead to pathological states when dysregulated. The two systems have been shown to mediate the therapeutic effect of antidepressant drugs and to regulate hippocampal neurogenesis. To elucidate the interplay of both systems at cellular and behavioral levels, we generated a transgenic mouse line that overexpresses BDNF in serotonergic neurons in an inducible manner. Besides displaying enhanced hippocampus-dependent contextual learning, transgenic mice were less affected by chronic social defeat stress (CSDS) compared to wild-type animals. In parallel, we observed enhanced serotonergic axonal sprouting in the dentate gyrus and increased neural stem/progenitor cell proliferation, which was uniformly distributed along the dorsoventral axis of the hippocampus. In the forced swim test, BDNF-overexpressing mice behaved similarly as wild-type mice treated with the antidepressant fluoxetine. Our data suggest that BDNF released from serotonergic projections exerts this effect partly by enhancing adult neurogenesis. Furthermore, independently of the genotype, enhanced neurogenesis positively correlated with the social interaction time after the CSDS, a measure for stress resilience.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neurônios Serotoninérgicos , Animais , Antidepressivos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurogênese/fisiologia , Neurônios Serotoninérgicos/metabolismo
12.
Naunyn Schmiedebergs Arch Pharmacol ; 395(10): 1189-1207, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35876905

RESUMO

Depression and coronary heart diseases are the common comorbid disorder affecting humans globally. The present study evaluated the effectiveness of rosmarinic acid (RA) against myocardial infarction (MI) in comorbid depression induced by maternal separation in rats. Maternal stress is one of the childhood crises that may be a potential risk factor for coronary heart disease in later part of life. As per protocol, 70-80% of pups were separated daily for 3 h between postnatal day 1 (PND1) and postnatal day 21 (PND21). Forced-swim test, sucrose preference test, and electrocardiography were performed during the experiment. Body weight was measured on PND0, PND35, and PND55. Orally rosmarinic acid (25 mg/kg and 50 mg/kg) and fluoxetine (10 mg/kg) was done from PND35 to PND55. On PND53 and PND54, isoproterenol (100 mg/kg, subcutaneously) was administered to induce myocardial infarction. On PND55, blood was collected and animals sacrificed, and plasma corticosterone, brain-derived neurotrophic factor, cardiac biomarkers, interleukine-10, and anti-oxidant parameters were measured. Rosmarinic acid and fluoxetine ameliorated the maternal separation-induced increase in immobility period, anhedonia, body weight, ST elevation, corticosterone, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). At the same time, both drugs elevated the tissue levels of BDNF, IL-10, glutathione, and superoxide dismutase activity. This study provides the first experimental evidence that maternal stress is an independent risk factor of cardiac abnormalities in rats. Moreover, maternal stress synergistically increases the severity of cardiac abnormalities induced by isoproterenol. Interestingly, fluoxetine and rosmarinic acid effectively ameliorated behavioral anomalies and myocardial infarction in maternally separated rats. Schematic representation of possible molecular mechanism of action of rosmarinic acid against MS-induced myocardial infarction. RA, rosmarinic acid; MS, maternal separation; PND, postnatal days; ISO, isoproterenol; BDNF, brain-derived neurotrophic factor; GSH, glutathione; SOD, superoxide dismutase; IL-10, interleukin-10; MI, myocardial infarction.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Infarto do Miocárdio , Animais , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cinamatos , Corticosterona/farmacologia , Depsídeos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Glutationa/metabolismo , Interleucina-10/metabolismo , Isoproterenol/farmacologia , Privação Materna , Miocárdio/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
13.
J Neurochem ; 162(5): 404-416, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35736504

RESUMO

Selective serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed treatments for depression, but their effects on serotonin reuptake and release are not well understood. Drosophila melanogaster, the fruit fly, expresses the serotonin transporter (dSERT), the major target of SSRIs, but real-time serotonin changes after SSRIs have not been characterized in this model. The goal of this study was to characterize effects of SSRIs on serotonin concentration and reuptake in Drosophila larvae. We applied various doses (0.1-100 µM) of fluoxetine (Prozac), escitalopram (Lexapro), citalopram (Celexa), and paroxetine (Paxil), to ventral nerve cord (VNC) tissue and measured optogenetically-stimulated serotonin release with fast-scan cyclic voltammetry (FSCV). Fluoxetine increased reuptake from 1 to 100 µM, but serotonin concentration only increased at 100 µM. Thus, fluoxetine occupies dSERT and slows clearance but does not affect concentration. Escitalopram and paroxetine increased serotonin concentrations at all doses, but escitalopram increased reuptake more. Citalopram showed lower concentration changes and faster reuptake profiles compared with escitalopram, so the racemic mixture of citalopram does not change reuptake as much as the S-isomer. Dose response curves were constructed to compare dSERT affinities and paroxetine showed the highest affinity and fluoxetine the lowest. These data demonstrate SSRI mechanisms are complex, with separate effects on reuptake or release. Furthermore, dynamic serotonin changes in Drosophila are similar to previous studies in mammals. This work establishes how antidepressants affect serotonin in real-time, which is useful for future studies that will investigate pharmacological effects of SSRIs with different genetic mutations in Drosophila.


Assuntos
Citalopram , Inibidores de Captação de Serotonina , Animais , Antidepressivos/farmacologia , Citalopram/farmacologia , Drosophila , Drosophila melanogaster , Fluoxetina/farmacologia , Mamíferos , Paroxetina/farmacologia , Serotonina , Inibidores de Captação de Serotonina/farmacologia
15.
Life Sci ; 304: 120679, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35662648

RESUMO

PURPOSES: Hepatic bioactivation of fluoxetine (FXN) could increase free radicals' generation provoking hepatotoxicity. Therefore, the protective effects of ellagic acid (EA) and taurine (TAU) treatments against fluoxetine-induced liver damage in rats were examined. MATERIALS AND METHODS: Sixty four male Wistar rats were randomly assigned to 8 groups (n = 8). Group (1) Control, group (2) FXN, group (3) FXN + EA, group (4) FXN + TAU, group (5) FXN + EA + TAU, group (6) EA, group (7) TAU, and group (8) EA + TAU. Then, the serum and tissue parameters of the oxidative stress were examined. KEY FINDINGS: FXN significantly raised serum MDA, protein carbonyl, lipid profile, ALT, AST, ALP, total bilirubin, serum IL-1ß; and gene expressions of IL-1ß, NF-κB, and TNF-α. Moreover, it significantly decreased HDL-C, ferric reducing antioxidant power (FRAP), catalase activity, vitamin C, and SOD activity in the liver compared to group 1. When compared to group 2, EA and TAU treatment dramatically increased antioxidant capacity and lowered hepatotoxic biochemical markers and cellular inflammation. Results also showed a protective effect of treatment against oxidative damage caused by hepatocytes' cytoarchitecture. SIGNIFICANCE: Our study concluded the beneficial effects of EA and TAU on FXN-induced hepatotoxicity. These effects were derived from free radical scavenging properties and the anti-inflammatory effects related to IL-1ß, NF-κB, and TNF-α gene expression inhibition.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Ácido Elágico , Fluoxetina , NF-kappa B , Taurina , Fator de Necrose Tumoral alfa , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ácido Elágico/farmacologia , Fluoxetina/farmacocinética , Fluoxetina/farmacologia , Masculino , NF-kappa B/biossíntese , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Taurina/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Theranostics ; 12(8): 3656-3675, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664081

RESUMO

Background: Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Methods: Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Results: Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Conclusion: Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.


Assuntos
Ansiolíticos , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Fluoxetina/metabolismo , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo I/metabolismo
17.
Chem Biol Interact ; 363: 110030, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35760085

RESUMO

Some drugs that act on the central nervous system (CNS) are known to affect the endocrine system, although the mechanisms of endocrine toxicity are not well characterized to date. Such CNS drugs include antipsychotics, anticonvulsants, and antidepressants. In the present study, in-vitro firefly luciferase reporter-gene assays using the AR-EcoScreen assay using Chinese hamster ovary (CHO) cell line, hERα-HeLa9903, MDA-kb2, and GH3.TRE-Luc cell lines were used to determine the effects of nine CNS drugs on the androgen receptor, estrogen receptor α, glucocorticoid receptor, and thyroid hormone receptor, respectively. In the AR-EcoScreen assay using CHO cells, anti-androgenic activities were shown for carbamazepine (IC50, 167 µM), clonazepam (IC50, 26.7 µM), eslicarbazepine acetate (IC50, 375 µM), fluoxetine (at 25 µM), lorazepam (IC50, 16.4 µM), and sertraline (IC50, 8.7 µM). In the hERα-HeLa-9903 cells, estrogen receptor α agonistic activities were shown for fluoxetine, paroxetine, and sertraline (at 10 µM and 25 µM), and in the GH3.TRE-Luc cells, the same three CNS drugs showed antithyroid activities (IC50s, 11.6, 11.9, 2.7 µM, respectively). In the hERα-HeLa-9903 cells, estrogen receptor α antagonistic activities were shown for carbamazepine (IC50, 114.3 µM), clonazepam (IC50, 52.9 µM), and eslicarbazepine acetate (IC50, 376.6 µM). When the CNS drugs were tested in the MDA-kb2 cells, none of them showed any activities toward glucocorticoid receptors. Little to no effects were seen toward any of these nuclear receptors for paliperidone and risperidone. The increased signal in the estrogen receptor α agonism assay seen for fluoxetine and paroxetine was confirmed to be mediated through estrogen receptor α. Additionally, we examined the interference of these CNS drugs with the firefly luciferase enzyme. These data elucidate the potential for adverse endocrine effects for some of these CNS drugs, which should therefore contribute to informed choice when prescribing them. However, long-term exposure to therapeutic concentrations of CNS drugs that have activities on the endocrine system should be explored further also in vivo.


Assuntos
Androgênios , Receptor alfa de Estrogênio , Animais , Células CHO , Carbamazepina , Fármacos do Sistema Nervoso Central , Clonazepam , Cricetinae , Cricetulus , Estrogênios , Fluoxetina/farmacologia , Glucocorticoides , Luciferases de Vaga-Lume , Paroxetina , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Sertralina , Glândula Tireoide/metabolismo
18.
J Trauma Acute Care Surg ; 93(1): 38-42, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35727591

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in trauma patients worldwide. Brain injury is associated with significant inflammation, both within the brain and in the peripheral organs. This inflammatory response in TBI leads to a secondary injury, worsening the effects of the original brain injury. Serotonin is also linked to inflammation in the intestine and inflammatory bowel disease, but its role in the gut-brain axis is not known. We hypothesized that using fluoxetine to block serotonin reuptake would reduce organ inflammation and improve outcomes after TBI. METHODS: C57/B6 mice were given a severe TBI using a controlled cortical impact. To measure intestinal permeability, a piece of terminal ileum was resected, the lumen was filled with 4-kDa fluorescein isothiocyanate (FITC)-dextran, and the ends were tied. The intestinal segment was submerged in buffer and fluorescence in the buffer measured over time. To measure lung permeability, 70-kDa FITC-dextran is injected retro-orbitally. Thirty minutes later, the left lung was homogenized and the fluorescence was measured. To measure performance on the rota-rod, mice were placed on a spinning rod, and the time to fall off was measured. Those treated with fluoxetine received a single dose of 5 mg/kg via intraperitoneal injection immediately after injury. RESULTS: Traumatic brain injury was associated with an increase in intestinal permeability to FITC-dextran, increased lung vascular permeability, and worse performance on the rota-rod. Fluoxetine significantly reduced lung and intestinal permeability after TBI and improved performance on the rota-rod after TBI. CONCLUSION: Use of fluoxetine has the potential to reduce lung injury and improve motor coordination in severe TBI patients. Further study will be needed to elucidate the mechanism behind this effect.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Animais , Lesões Encefálicas/complicações , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Modelos Animais de Doenças , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Humanos , Inflamação/complicações , Camundongos , Serotonina/uso terapêutico
19.
Sci Rep ; 12(1): 9591, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688860

RESUMO

Drug resistance in tuberculosis is exacerbating the threat this disease is posing to human beings. Antibiotics that were once effective against the causative agent, Mycobacterium tuberculosis (Mtb), are now no longer usable against multi- and extensively drug-resistant strains of this pathogen. To address this issue, new drug combinations and novel methods for targeted drug delivery could be of considerable value. In addition, studies have shown that the use of the antidepressant drug fluoxetine, a serotonin reuptake inhibitor, can be useful in the treatment of infectious diseases, including bacterial infections. In this study, an isoniazid and fluoxetine-conjugated multi-walled carbon nanotube nanofluid were designed to increase drug delivery efficiency alongside eliminating drug resistance in vitro. The prepared nanofluid was tested against Mtb. Expression levels of inhA and katG mRNAs were detected by Real-time PCR. ELISA was applied to measure levels of cytokine secretion (TNF-α, and IL-6) from infected macrophages treated with the nano delivery system. The results showed that these nano-drug delivery systems are effective for fluoxetine at far lower doses than for free drugs. Fluoxetine also has an additive effect on the effect of isoniazid, and their concomitant use in the delivery system can have significant effects in treating infection of all clinical strains of Mtb. In addition, it was found that the expression of isoniazid resistance genes, including inhA, katG, and the secretion of cytokines TNFα and IL6 under the influence of this drug delivery system is well regulated. It was shown that the drug conjugation can improve the antibacterial activity of them in all strains and these two drugs have an additive effect on each other both in free and conjugated forms. This nano-drug delivery method combined with host targeted molecules could be a game-changer in the development of a new generation of antibiotics that have high therapeutic efficiencies, low side effects, and the potential to overcome the problem of drug resistance.


Assuntos
Mycobacterium tuberculosis , Nanopartículas , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/genética , Fluoxetina/farmacologia , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Testes de Sensibilidade Microbiana , Mutação , Nanopartículas/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
20.
J Appl Physiol (1985) ; 133(2): 371-389, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35708704

RESUMO

Serotonin (5-HT) is an important modulator of brain networks that control breathing. The selective serotonin reuptake inhibitor fluoxetine (FLX) is the first-line antidepressant drug prescribed during pregnancy. We investigated the effects of prenatal FLX exposure on baseline breathing, ventilatory and metabolic responses to hypercapnia and hypoxia as well as number of brainstem 5-HT and tyrosine hydroxylase (TH) neurons of rats during postnatal development (P0-82). Prenatal FLX exposure of males showed a lower baseline V̇e that appeared in juveniles and remained in adulthood, with no sleep-wake state dependency. Prenatal FLX exposure of females did not affect baseline breathing. Juvenile male FLX showed increased CO2 and hypoxic ventilatory responses, normalizing by adulthood. Alterations in juvenile FLX-treated males were associated with a greater number of 5-HT neurons in the raphe obscurus (ROB) and raphe magnus (RMAG). Adult FLX-exposed males showed greater number of 5-HT neurons in the raphe pallidus (RPA) and TH neurons in the A5, whereas reduced number of TH neurons in A7. Prenatal FLX exposure of female rats was associated with greater hyperventilation induced by hypercapnia at P0-2 and juveniles, whereas P12-14 and adult FLX (non-rapid eye movement, NREM sleep) rats showed an attenuation of the hyperventilation induced by CO2. FLX-exposed females had fewer 5-HT neurons in the RPA and reduced TH A6 density at P0-2; and greater number of TH neurons in the A7 at P12-14. These data indicate that prenatal FLX exposure affects the number of some monoaminergic regions in the brain and results in long-lasting, sex-specific changes in baseline breathing pattern and ventilatory responses to respiratory challenges.NEW & NOTEWORTHY Selective serotonin reuptake inhibitors (SSRIs) readily cross the placental and the fetal blood-brain barrier where it will affect 5-HT levels in the developing brain. Although SSRI is used during pregnancy, there are no studies showing SSRI exposure during late pregnancy and postnatal effects on breathing control in males and females. We demonstrated that fluoxetine exposure during late pregnancy in rats was associated with long-lasting, sex-specific effects on breathing and brainstem monoaminergic groups.


Assuntos
Fluoxetina , Efeitos Tardios da Exposição Pré-Natal , Animais , Dióxido de Carbono , Feminino , Fluoxetina/farmacologia , Humanos , Hipercapnia , Hiperventilação , Masculino , Placenta/metabolismo , Gravidez , Ratos , Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia
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