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Biochemical Pharmacology Oct 2023Prolonged vasoconstrictor signalling found in hypertension, increases arterial contraction, and alters vessel architecture by stimulating arterial smooth muscle cell...
Prolonged vasoconstrictor signalling found in hypertension, increases arterial contraction, and alters vessel architecture by stimulating arterial smooth muscle cell (ASMC) growth, underpinning the development of re-stenosis lesions and vascular remodelling. Vasoconstrictors interact with their cognate G protein coupled receptors activating a variety of signalling pathways to promote smooth muscle proliferation. Here, angiotensin II (AngII) and endothelin 1 (ET1), but not UTP stimulates ASMC proliferation. Moreover, siRNA-mediated depletion of endogenous GRK2 expression, or GRK2 inhibitors, compound 101 or paroxetine, prevented AngII and ET1-promoted ASMC growth. Depletion of GRK2 expression or inhibition of GRK2 activity ablated the prolonged phase of AngII and ET-stimulated ERK signalling, while enhancing and prolonging UTP-stimulated ERK signalling. Increased GRK2 expression enhanced and prolonged AngII and ET1-stimulated ERK signalling, but suppressed UTP-stimulated ERK signalling. In ASMC prepared from 6-week-old WKY and SHR, AngII and ET1-stimulated proliferation rates were similar, however, in cultures prepared from 12-week-old rats AngII and ET1-stimulated growth was enhanced in SHR-derived ASMC, which was reversed following depletion of GRK2 expression. Furthermore, in ASMC cultures isolated from 6-week-old WKY and SHR rats, AngII and ET1-stimulated ERK signals were similar, while in cultures from 12-week-old rats ERK signals were both enhanced and prolonged in SHR-derived ASMC, and were reversed to those seen in age-matched WKY-derived ASMC following pre-treatment of SHR-derived ASMC with compound 101. These data indicate that the presence of GRK2 and its catalytic activity are essential to enable pro-proliferative vasoconstrictors to promote growth via recruitment and activation of the ERK signalling pathway in ASMC.
Topics: Animals; Rats; Angiotensin II; Cell Proliferation; Cells, Cultured; Hypertension; Muscle, Smooth, Vascular; Rats, Inbred SHR; Rats, Inbred WKY; Uridine Triphosphate; Vasoconstrictor Agents; G-Protein-Coupled Receptor Kinase 2
PubMed: 37690571
DOI: 10.1016/j.bcp.2023.115795 -
Biomedicine & Pharmacotherapy =... Aug 2023In this study, we have investigated the anti-depressant effects of the fruit Areca catechu L. (ACL) and elucidated its potential underlying mechanism using a rat model...
OBJECTIVES
In this study, we have investigated the anti-depressant effects of the fruit Areca catechu L. (ACL) and elucidated its potential underlying mechanism using a rat model of chronic unpredictable mild stress (CUMS).
METHODS
CUMS was induced in rats to establish a depression animal model for 28 days. According to the baseline sucrose preference, the male rats were divided into 6 different groups. They were treated with paroxetine hydrochloride, ACL, and water once a day until the behavioral tests were performed. The levels of corticosterone (CORT), malondialdehyde (MDA), catalase (CAT), and total superoxide dismutase (T-SOD) in serum were detected using a commercial kit, and the concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) monoamine neurotransmitters in the brain tissues were detected by liquid chromatography-tandem mass spectrometry. doublecortin (DCX) expression in the hippocampal dentate gyrus (DG) was determined by immunofluorescence, and the relative abundance of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β of brain tissues were assayed by western blot.
RESULTS
ACL markedly increased sucrose preference, decreased the immobility time, and shortened the feeding latency of CUMS-induced rats. CUMS induction resulted in marked changes in the contents of the monoamine neurotransmitters (5-HT and DA) in the hippocampus and cortex of brain tissues and the levels of CORT, MDA, CAT, and T-SOD in serum, whereas ACL administration alleviated these considerable changes. ACL promoted DCX expression in DG and increased the protein levels of BDNF, TrkB, PI3K, p-AKT/AKT, PSD-95, and p-GSK-3β/GSK-3β in the brains of CUMS-induced rats.
CONCLUSIONS
Our results indicated that ACL may improve depression-like behaviors in CUMS-induced rats by decreasing the hyperfunction and oxidative stress of the hypothalamic-pituitary-adrenal axis, stimulating hippocampal neurogenesis, and activating the BDNF signaling pathway.
Topics: Rats; Male; Animals; Depression; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Areca; Glycogen Synthase Kinase 3 beta; Hypothalamo-Hypophyseal System; Proto-Oncogene Proteins c-akt; Serotonin; Pituitary-Adrenal System; Signal Transduction; Hippocampus; Corticosterone; Dopamine; Sucrose; Neurotransmitter Agents; Phosphatidylinositol 3-Kinases; Stress, Psychological; Disease Models, Animal; Behavior, Animal
PubMed: 37245336
DOI: 10.1016/j.biopha.2023.114459 -
Andrology Mar 2024Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes...
BACKGROUND
Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes are still unclear.
OBJECTIVES
Paroxetine serotonergic effects in testes were evaluated, focusing on steroidogenesis and the correlation between macrophages population and possible TNF-α-derived oxidative stress. We also verified whether the changes are reversible following treatment interruption.
MATERIALS AND METHODS
Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL germ cells, M1 (CD68 ), and M2 (Perls ) macrophages were quantified. 17β-HSD7, CYP19A1, NDRG2, oxytocin, TNF-α, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed.
RESULTS
The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls macrophages. TUNEL germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17β-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-α and iNOS. Esr1 and Tnfa overexpression and increased number of CD68 macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65.
CONCLUSIONS
Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin-estrogen pathways may be responsible for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin/estrogen effects.
Topics: Male; Rats; Animals; Testis; Paroxetine; Serotonin; Tumor Necrosis Factor-alpha; Oxytocin; Nitrites; Semen; Testosterone; Estrogens; Macrophages; Malondialdehyde
PubMed: 37675929
DOI: 10.1111/andr.13513 -
Clinical Psychopharmacology and... Aug 2023Restless legs syndrome (RLS) is a chronic progressive movement disorder characterized by abnormal sensations, especially at rest and at night, as the need and urge to...
Restless legs syndrome (RLS) is a chronic progressive movement disorder characterized by abnormal sensations, especially at rest and at night, as the need and urge to move the lower extremity. It has been reported that RLS severity and frequency increase in patients with anxiety and depression. It has been reported that serotonin-noradrenaline reuptake inhibitors such as venlafaxine and selective serotonin reuptake inhibitors such as citalopram, fluoxetine, paroxetine, and sertraline can cause RLS symptoms. No adverse effects of vortioxetine on RLS have been reported in the literature. In this case series, we report the effect of vortioxetine in patients with RLS with symptoms of depression and anxiety. In this case series, the effect of adding vortioxetine to treatment on RLS symptoms is reported in 7 patients (5 female). After the use of vortioxetine, 5 of 7 patients' symptoms regressed without the need to start a separate drug for primary movement disorder. In conclusion, we believe that studies should be conducted to investigate the efficacy of vortioxetine in the treatment of RLS. Therefore, randomized controlled studies are needed to determine the effect and safety of vortioxetine on RLS symptoms.
PubMed: 37424427
DOI: 10.9758/cpn.22.1021 -
Current Neuropharmacology 2024Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate... (Review)
Review
Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.
Topics: Humans; Stress Disorders, Post-Traumatic; Paroxetine; Amitriptyline; Sleep Initiation and Maintenance Disorders; Sleepiness; Systematic Reviews as Topic; Antidepressive Agents
PubMed: 37533247
DOI: 10.2174/1570159X21666230801144328 -
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 -
Journal of Addictive Diseases Jul 2023Gambling disorder (GD) is a psychiatric disorder classified in the DSM-5 as a non-substance-related and addictive disorder with extensive health and socioeconomic...
BACKGROUND
Gambling disorder (GD) is a psychiatric disorder classified in the DSM-5 as a non-substance-related and addictive disorder with extensive health and socioeconomic impacts. Its chronic and high-relapsing nature makes it essential to find treatment strategies that improve functioning and reduce impairment associated with it. The purpose of this narrative review is to evaluate and summarize the available evidence on the effectiveness and safety of pharmacotherapy in GD.
METHODS
An electronic literature search of Medline, Embase, and Cochrane Central was conducted to identify systematic reviews, meta-analyses, and reviews on pharmacological interventions in patients with gambling disorder. A similar search of these databases and of Prospero, Clinicaltrials.gov, and Epistemonikos was conducted to identify clinical trials that were published since 2019.
RESULTS
The initial search identified 1925 articles. After screening and duplicate removal, 18 articles were included in the review (11 studies were systematic reviews and meta-analyses, 6 were reviews, and 1 was an open-label trial). Eight pharmacological agents (naltrexone, nalmefene, paroxetine, fluvoxamine, citalopram, escitalopram, lithium, and topiramate that were studied in randomized controlled trials and open-label trials showed small to moderate effect sizes in reducing GD symptoms in some studies during post-hoc analyses.
CONCLUSION
The overall sum of evidence in the literature on the use of pharmacotherapy in GD is conflicting and inconclusive. Some studies have shown that pharmacotherapy's role in GD is promising, especially when the choice of the agent is guided by comorbid psychiatric disorders. However, significant limitations exist in the study designs, which need to be addressed in future research on the topic. Conducting future and more rigorous trials that address the limitations in the existing literature is necessary to establish more accurate efficacy data on the use of pharmacotherapy in this population.
PubMed: 37423770
DOI: 10.1080/10550887.2023.2229725 -
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 -
EBioMedicine Jun 2024Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. (Meta-Analysis)
Meta-Analysis
Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.
BACKGROUND
Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing.
METHODS
We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses.
FINDINGS
After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population.
INTERPRETATION
Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach.
FUNDING
National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.
Topics: Adult; Female; Humans; Male; Middle Aged; Anxiety Disorders; China; Cytochrome P-450 CYP2D6; Depressive Disorder; East Asian People; Genotype; Paroxetine; Polymorphism, Single Nucleotide; Prospective Studies; Treatment Outcome
PubMed: 38776596
DOI: 10.1016/j.ebiom.2024.105165 -
Expert Review of Neurotherapeutics Jul 2024Despite its milder severity, the chronic nature of dysthymia leads to significant impairments and functional limitations. The treatment of dysthymia has received... (Review)
Review
INTRODUCTION
Despite its milder severity, the chronic nature of dysthymia leads to significant impairments and functional limitations. The treatment of dysthymia has received considerably less research attention compared to major depressive disorder (MDD).
AREAS COVERED
The authors have conducted a comprehensive review on the treatment of dysthymia. Their primary objective was to identify therapeutic options that have demonstrated genuine efficacy. To do this, they searched the PubMed database, without any time restrictions, to retrieve original studies. The samples were exclusively comprised individuals diagnosed with dysthymia according to the diagnostic criteria outlined in DSM-III, DSM-III-R, DSM-IV, or DSM-IV-TR.
EXPERT OPINION
Within the realm of dysthymia treatment, several antidepressants, including imipramine, sertraline, paroxetine, minaprine, moclobemide, and amineptine, in addition to the antipsychotic agent amisulpride, have demonstrated superiority over placebo. In certain studies, psychotherapeutic interventions did not distinguish themselves significantly from pharmacological treatments and failed to exhibit greater efficacy than a placebo. However, these findings remain inconclusive due to the limited number of studies and substantial methodological limitations prevalent in a significant proportion of them. Limitations include factors like small sample sizes, the absence of placebo comparisons, and a lack of study blinding.
Topics: Humans; Dysthymic Disorder; Antidepressive Agents; Antipsychotic Agents; Psychotherapy
PubMed: 38805342
DOI: 10.1080/14737175.2024.2360671