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Aging Oct 2023G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary...
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Transforming Growth Factor beta1; Paroxetine; Lung; Fibroblasts; Collagen; Mice, Inbred C57BL
PubMed: 37815883
DOI: 10.18632/aging.205092 -
Parasites & Vectors Jan 2021Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter,...
BACKGROUND
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.
METHODS
To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.
RESULTS
We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.
CONCLUSIONS
Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.
Topics: Animals; Cell Proliferation; Echinococcus multilocularis; Gene Expression; Gene Expression Profiling; Helminth Proteins; In Situ Hybridization; Larva; Nervous System; Paroxetine; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 33407815
DOI: 10.1186/s13071-020-04533-0 -
Frontiers in Psychiatry 2019Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline... (Review)
Review
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021. www.ClinicalTrials.gov, identifiers NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
PubMed: 31572236
DOI: 10.3389/fpsyt.2019.00650 -
Future Microbiology May 2023To evaluate the antibacterial activity of paroxetine alone and associated with oxacillin against isolates of methicillin-sensitive and -resistant . The broth...
To evaluate the antibacterial activity of paroxetine alone and associated with oxacillin against isolates of methicillin-sensitive and -resistant . The broth microdilution and checkerboard techniques were used, with investigation of possible mechanisms of action through flow cytometry, fluorescence microscopy and molecular docking, in addition to scanning electron microscopy for morphological analysis. Paroxetine showed a MIC of 64 μg/ml and bactericidal activity, mostly additive interactions in combination with oxacillin, evidence of action on genetic material and membrane, morphological changes in microbial cells and influence on virulence factors. Paroxetine has antibacterial potential from the perspective of drug repositioning.
Topics: Humans; Staphylococcus aureus; Paroxetine; Methicillin-Resistant Staphylococcus aureus; Molecular Docking Simulation; Anti-Bacterial Agents; Oxacillin; Staphylococcal Infections; Microbial Sensitivity Tests
PubMed: 37213136
DOI: 10.2217/fmb-2022-0232 -
Journal of the American Board of Family... Jan 2024Existing guidelines for primary care clinicians (PCCs) on the detection and management of perinatal depression (PD) contain important gaps. This review aims to provide... (Review)
Review
INTRODUCTION
Existing guidelines for primary care clinicians (PCCs) on the detection and management of perinatal depression (PD) contain important gaps. This review aims to provide PCCs with a summary of clinically relevant evidence in the field.
METHODS
A narrative literature review was conducted by searching PubMed and PsycINFO for articles published between 2010 to 2023. Guidelines, systematic reviews, clinical trials, and/or observational studies were all examined.
RESULTS
Screening with the Edinburgh Postnatal Depression Scale or Patient Health Questionnaire-9 followed by a diagnostic evaluation for major depressive disorder in probable cases can enhance PD detection. At-risk individuals and mild to moderate PD should be referred for cognitive behavioral therapy or interpersonal psychotherapy when available. Selective serotonin reuptake inhibitors should be used for moderate to severe PD, with sertraline, escitalopram, or citalopram being preferred first. Using paroxetine or clomipramine in pregnancy, and fluoxetine or doxepin during lactation is generally not preferred. Gestational antidepressant use is associated with a small increase in risk of reduced gestational age at birth, low birth weight, and lower APGAR scores, though whether these links are causal is unclear. Sertraline and paroxetine have the lowest rate of adverse events during lactation. Consequences of untreated PD can include maternal and offspring mortality, perinatal complications, poor maternal-infant attachment, child morbidity and maltreatment, less breastfeeding, and offspring developmental problems.
CONCLUSIONS
These clinically relevant data can support the delivery of high-quality care by PCCs. Risks and benefits of PD treatments and the consequences of untreated PD should be discussed with patients to support informed decision making.
Topics: Pregnancy; Infant, Newborn; Female; Child; Humans; Paroxetine; Sertraline; Depression; Depressive Disorder, Major; Primary Health Care
PubMed: 37704392
DOI: 10.3122/jabfm.2023.230061R1 -
Progress in Neuro-psychopharmacology &... Jul 2023Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship violence, combat exposure, witnessing death, or serious injury. This study aimed to identify the most suitable drugs for the management of PTSD based on a network meta-analysis (NMA).
METHODS
Six databases (Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and Web of Science) were searched from inception to September 6, 2022.
RESULTS
Thirty articles with a total of 5170 participants were included. Compared with placebo, active drugs including olanzapine (SMD = -0.66, 95% CI: -1.19 to -0.13), risperidone (SMD = -0.23, 95% CI: -0.42 to -0.03), quetiapine (SMD = -0.49, 95% CI: -0.93 to -0.04), venlafaxine (SMD = -0.29, 95% CI: -0.42 to -0.16), sertraline (SMD = -0.23, 95% CI: -0.34 to -0.11), paroxetine (SMD = -0.48, 95% CI: -0.60 to -0.36) and fluoxetine (SMD = -0.27, 95% CI: -0.42 to -0.12), significantly reduced the total clinician-administered PTSD scale score.
CONCLUSION
The results of this study support the use of paroxetine, venlafaxine, and quetiapine as first-line treatment for PTSD. In addition, quetiapine is recommended for patients with PTSD affected by symptoms of hyperarousal and re-experience disorder. Clinicians should prescribe medications based on the severity of PTSD symptoms and other conditions to develop the best treatment strategy for this patient population.
Topics: Humans; Stress Disorders, Post-Traumatic; Cognitive Behavioral Therapy; Paroxetine; Quetiapine Fumarate; Venlafaxine Hydrochloride; Network Meta-Analysis
PubMed: 36934999
DOI: 10.1016/j.pnpbp.2023.110754 -
Journal of Psychopharmacology (Oxford,... Aug 2021Antidepressant drugs in adolescent depression are sometimes mired by efficacy issues and paradoxical effects. Transcranial direct current stimulation (tDCS) could...
BACKGROUND
Antidepressant drugs in adolescent depression are sometimes mired by efficacy issues and paradoxical effects. Transcranial direct current stimulation (tDCS) could represent an alternative.
AIMS/METHODS
We tested the antidepressant action of prefrontal tDCS and paroxetine (20 mg/kg, intraperitoneal) in olfactory bulbectomised (OBX) adolescent rats. Using enzyme-linked immunosorbent assays and in situ hybridisation, we examined treatment-induced changes in plasma brain-derived neurotrophic factor (BDNF) and brain serotonin transporter (SERT) and 5-HT-1A mRNA.
RESULTS
OBX-induced anhedonia-like reductions in sucrose preference (SP) correlated with open field (OF) hyperactivity. These were accompanied by decreased zif268 mRNA in the piriform/amygdalopiriform transition area, and increased zif268 mRNA in the hypothalamus. Acute paroxetine (2 days) led to a profound SP reduction, an effect blocked by combined tDCS-paroxetine administration. Chronic (14 days) tDCS attenuated hyperlocomotion and its combination with paroxetine blocked OBX-induced SP reduction. Correlations among BDNF, SP and hyperlocomotion scores were altered by OBX but were normalised by tDCS-paroxetine co-treatment. In the brain, paroxetine increased zif268 mRNA in the hippocampal CA1 subregion and decreased it in the claustrum. This effect was blocked by tDCS co-administration, which also increased zif268 in CA2. tDCS-paroxetine co-treatment had variable effects on 5-HT1A receptors and SERT mRNA. 5-HT1A receptor changes were found exclusively within depression-related parahippocampal/hippocampal subregions, and SERT changes within fear/defensive response-modulating brainstem circuits.
CONCLUSION
These findings point towards potential synergistic efficacies of tDCS and paroxetine in the OBX model of adolescent depression via mechanisms associated with altered expression of BDNF, 5-HT1A, SERT and zif268 in discrete corticolimbic areas.
Topics: Animals; Brain-Derived Neurotrophic Factor; Combined Modality Therapy; Depression; Disease Models, Animal; Male; Olfactory Bulb; Paroxetine; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors; Transcranial Direct Current Stimulation
PubMed: 33908307
DOI: 10.1177/02698811211000765 -
European Journal of Drug Metabolism and... Sep 2022Herein, hydroxylation activities at the 6β-position and 21-position of progesterone mediated by human cytochrome P450 (CYP) 2D6 and its variants and the effects of...
BACKGROUND AND OBJECTIVES
Herein, hydroxylation activities at the 6β-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, 6β- and 21-hydroxyprogesterone levels were determined by high-performance liquid chromatography.
RESULTS
Although the Michaelis-Menten constants (K) for progesterone 6β- and 21-hydroxylation reactions mediated by the different CYP2D6 variants were similar, the maximal velocity (V) 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 6β- and/or 21-hydroxylation reactions mediated by CYP2D6.1 and CYP2D6.2 showed the highest V/K 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 K value for CYP2D6.2 was elevated in the presence of fluoxetine, whereas the value for CYP2D6.1 was unaltered; however, V 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.
Topics: Humans; Cytochrome P-450 CYP2D6; Fluoxetine; Hydroxylation; Paroxetine; Progesterone; Psychotropic Drugs
PubMed: 35838883
DOI: 10.1007/s13318-022-00784-7 -
International Journal of Pharmaceutics Jun 2024Depression is one of the most common psychiatric disorders. Nanotechnology has emerged to optimize the pharmacological response. Therefore, the aim of this work was to...
Depression is one of the most common psychiatric disorders. Nanotechnology has emerged to optimize the pharmacological response. Therefore, the aim of this work was to develop and characterize liposomes and nanocapsules containing paroxetine hydrochloride and evaluate their antidepressant-like effect using the open field and tail suspension tests in mice. Liposomes and nanocapsules were prepared using the reverse-phase evaporation and nanoprecipitation methods, respectively. The particle size of the formulation ranged from 121.81 to 310.73 nm, the polydispersity index from 0.096 to 0.303, the zeta potential from -11.94 to -34.50 mV, the pH from 5.31 to 7.38, the drug content from 80.82 to 94.36 %, and the association efficiency was 98 %. Paroxetine hydrochloride showed slower release when associated with liposomes (43.82 %) compared to nanocapsules (95.59 %) after 10 h. In Vero cells, in vitro toxicity showed a concentration-dependent effect for paroxetine hydrochloride nanostructures. Both nanostructures decreased the immobility time in the TST at 2.5 mg/kg without affecting the number of crossings in the open field test, suggesting the antidepressant-like effect of paroxetine. In addition, the nanocapsules decreased the number of groomings, reinforcing the anxiolytic effect of this drug. These results suggest that the nanostructures were effective in preserving the antidepressant-like effect of paroxetine hydrochloride even at low doses.
PubMed: 38848799
DOI: 10.1016/j.ijpharm.2024.124304 -
Journal of Clinical Sleep Medicine :... Jul 2020Sexsomnia is a parasomnia consisting of sexual behavior during non-rapid eye movement sleep. To date, there have been 116 clinical cases of sexsomnia reported and most...
Sexsomnia is a parasomnia consisting of sexual behavior during non-rapid eye movement sleep. To date, there have been 116 clinical cases of sexsomnia reported and most were treated with clonazepam. We present a case of an adult male with sexsomnia that started during his college days. He presented to us because of problems in his current marriage arising from sexual behavior during sleep. Polysomnography revealed no significant sleep-disordered breathing, electroencephalography abnormality, or abnormal movement during non-rapid eye movement and rapid eye movement (REM) sleep. Alcohol consumption was reported to worsen his sexsomnia. To avoid the neuro-depressant effects of benzodiazepines, paroxetine was administered and resulted in complete resolution of sexsomnia.
Topics: Adult; Humans; Male; Parasomnias; Paroxetine; Polysomnography; Sleep; Sleep Apnea Syndromes
PubMed: 32672534
DOI: 10.5664/jcsm.8478