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Archivos Espanoles de Urologia Feb 2023The main pathological changes of hemorrhagic cystitis (HC) are bladder inflammation, bladder epithelial damage and mast cell infiltration. Tropisetron has been...
OBJECTIVE
The main pathological changes of hemorrhagic cystitis (HC) are bladder inflammation, bladder epithelial damage and mast cell infiltration. Tropisetron has been corroborate to conduct a protective role in HC, but its specific etiology remains unclear. The objective of this research was to estimate the mechanism of action of Tropisetron in haemorrhagic cystitis tissue.
METHODS
Cyclophosphamide (CTX) was utilized to induce the construction of HC rat model, and rats were handled with different doses of Tropisetron. The impact of Tropisetron on the expression of inflammatory factors and oxidative stress factors in the rats with cystitis were measured by western blot, as well as the related proteins of toll-like receptor 4/nuclear transcription factor-κB (TLR-4/NF-κB) and januskinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) pathways.
RESULTS
CTX-induced cystitis in rats was accompanied by notable pathological tissue damage and increased bladder wet weight ratio, elevated mast cell numbers and collagen fibrosis compared to controls. Tropisetron ameliorated CTX-induced injury in a concentration-dependent manner. Futhermore, CTX induced oxidative stress and inflammatory damage, while Tropisetron can alleviate these injuries. Besides, Tropisetron ameliorated CTX-induced cystitis by restraining TLR-4/NF-κB and JAK1/STAT3 signalling pathways.
CONCLUSIONS
Taken together, Tropisetron ameliorates cyclophosphamide-induced haemorrhagic cystitis via modulating TLR-4/NF-κB and JAK1/STAT3 signalling pathways. These findings carry important implication for the study of the molecular mechanisms of pharmacological treatment of hemorrhagic cystitis.
Topics: Animals; Rats; Cyclophosphamide; Cystitis; Hemorrhage; NF-kappa B; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 4; Tropisetron
PubMed: 36914420
DOI: 10.56434/j.arch.esp.urol.20237601.5 -
Cell Stress & Chaperones Jan 2021Tropisetron is a 5-HT3 receptor antagonist that exerts protective effect against DN. The aim of this study was to investigate the possible molecular mechanisms...
Tropisetron is a 5-HT3 receptor antagonist that exerts protective effect against DN. The aim of this study was to investigate the possible molecular mechanisms associated with the renoprotective effects of tropisetron in STZ-induced diabetic rats. Animals were subdivided into 5 equal groups; control, tropisetron, diabetes, tropisetron + diabetes, and glibenclamide + diabetes (n = 7). For induction of type 1 diabetes, a single injection of STZ (55 mg/kg, i.p.) was administered to the animals. Diabetic rats were treated with tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) for 2 weeks. According to the conducted analysis, diabetes led to renal dysfunction (reduction in glomerular filtration rate and urine urea and creatinine as well as elevation in plasma urea and creatinine) and abnormalities in antioxidant defense system (reduction in TAC and elevation in MDA), compared with the control group, which was prevented by tropisetron treatment. Reverse transcription-quantitative polymerase chain reaction and western blotting analysis demonstrated that SIRT1 gene expression decreased while FOXO3a and NF-κB gene expression as well as phosphorylated FOXO3a/total FOXO3a protein ratios and claudin-1 protein level increased in the kidney of diabetic rats compared with the control group. Herein, the results of this research showed that tropisetron treatment reversed these changes. Besides, all these changes were comparable with those produced by glibenclamide as a positive control. Hence, tropisetron ameliorated renal damage due to diabetic nephropathy possibly by suppressing oxidative stress and alteration of SIRT1, FOXO3a, and claudin-1 levels.
Topics: Animals; Claudin-1; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Forkhead Box Protein O3; Kidney; Male; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Sirtuin 1; Tropisetron
PubMed: 33047279
DOI: 10.1007/s12192-020-01170-5 -
Biomedicine & Pharmacotherapy =... Apr 20195-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current... (Review)
Review
5-HTR antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HTR itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HTR antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HTR antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HTR antagonists mediate the effects of nicotine could be attributed by both direct at 5-HTR and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HTR antagonist could be through α7 nAChR, 5-HT receptor (5-HTR), 5-HT receptor (5-HTR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HTR antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.
Topics: Humans; Palonosetron; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Tobacco Use Disorder
PubMed: 30797147
DOI: 10.1016/j.biopha.2019.108630 -
Neuropsychopharmacology : Official... Mar 2022Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for...
Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson's disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.
Topics: Antipsychotic Agents; Humans; Perception; Schizophrenia; Sensory Gating; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35017671
DOI: 10.1038/s41386-021-01255-4 -
PloS One 2021To determine the effectiveness of pharmacologic interventions for preventing postoperative nausea and vomiting (PONV) in patients undergoing thyroidectomy. (Comparative Study)
Comparative Study Meta-Analysis
OBJECTIVE
To determine the effectiveness of pharmacologic interventions for preventing postoperative nausea and vomiting (PONV) in patients undergoing thyroidectomy.
DESIGN
Systematic review and network meta-analysis (NMA).
DATA SOURCES
MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Google Scholar.
ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Randomized clinical trials that investigated the efficacy of pharmacologic interventions in preventing PONV in patients undergoing thyroidectomy were included. The primary endpoints were the incidences of postoperative nausea and vomiting (PONV), postoperative nausea (PON), postoperative vomiting (POV), use of rescue antiemetics, and incidence of complete response in the overall postoperative phases. The secondary endpoints were the same parameters assessed in the early, middle, and late postoperative phases. The surface under the cumulative ranking curve (SUCRA) values and rankograms were used to present the hierarchy of pharmacologic interventions.
RESULTS
Twenty-six studies (n = 3,467 patients) that investigated 17 different pharmacologic interventions were included. According to the SUCRA values, the incidence of PONV among the overall postoperative phases was lowest with propofol alone (16.1%), followed by palonosetron (27.5%), and with tropisetron (28.7%). The incidence of PON among the overall postoperative phases was lowest with propofol alone (11.8%), followed by tropisetron and propofol combination (14%), and ramosetron and dexamethasone combination (18.0%). The incidence of POV among the overall postoperative phases was lowest with tropisetron and propofol combination (2.2%), followed by ramosetron and dexamethasone combination (23.2%), and tropisetron alone (37.3%). The least usage of rescue antiemetics among the overall postoperative phases and the highest complete response was observed with tropisetron and propofol combination (3.9% and 96.6%, respectively).
CONCLUSION
Propofol and tropisetron alone and in combination, and the ramosetron and dexamethasone combination effectively prevented PONV, PON, POV in patients undergoing thyroidectomy, with some heterogeneity observed in this NMA of full-text reports. Their use minimized the need for rescue antiemetics and enhanced the complete response.
TRIAL REGISTRATION NUMBER
CRD42018100002.
Topics: Antiemetics; Drug Therapy, Combination; Humans; Network Meta-Analysis; Postoperative Nausea and Vomiting; Randomized Controlled Trials as Topic; Thyroidectomy; Treatment Outcome
PubMed: 33428643
DOI: 10.1371/journal.pone.0243865 -
Scientific Reports Nov 2023Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder, and selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of its... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in augmentation with selective serotonin reuptake inhibitors (SSRIs) in the treatment of moderate to severe obsessive-compulsive disorder: a systematic review and meta-analysis of randomized clinical trials.
Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder, and selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of its pharmacological treatment. About 40-60% of the cases are treatment-refractory, and this makes searching for second-line treatment necessary. 5-Hydroxytryptamine-3 (5-HT3) antagonists are among the many medications that have been used in augmentation with SSRIs. In this systematic review and meta-analysis, we assessed the efficacy and safety of 5-HT3 receptor antagonists in augmentation with SSRIs in treating moderate to severe OCD. We searched PubMed, Web of Science, Scopus, Cochrane library, and Google Scholar for relevant trials published up to December 2022. The effect size was the mean difference in Yale-Brown obsessive compulsive scale (Y-BOCS) scores before and after receiving 5-HT3 receptor antagonist drugs in augmentation with SSRIs in moderate to severe OCD patients. We included 6 randomized-controlled trails (RCTs) with 334 patients assessing the effect of the augmentation of SSRIs with ondansetron, granisetron, and tropisetron on treating moderate to severe OCD. Our results were in favor of the experimental group in total (Z = 8.37, P < 0.00001), in the compulsion subgroup (Z = 5.22, P < 0.00001), and in the obsession subgroup (Z = 8.33, P < 0.00001). They are well-tolerated, and have mild side effects and do not result in withdrawal. Augmentation of 5-HT3 antagonists with SSRIs can be beneficial in treating moderate to severe OCD. Further multi-center trials under adequate conditions in longer periods are needed to help come up with a comprehensive action plan.
Topics: Humans; Selective Serotonin Reuptake Inhibitors; Serotonin; Receptors, Serotonin, 5-HT3; Treatment Outcome; Randomized Controlled Trials as Topic; Obsessive-Compulsive Disorder; Drug Therapy, Combination
PubMed: 38012263
DOI: 10.1038/s41598-023-47931-x -
Drug Design, Development and Therapy 2023Perioperative multimodal analgesia can prevent chronic pain after breast cancer surgery. This study aimed to investigate the efficacy of combined perioperative oral... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Perioperative multimodal analgesia can prevent chronic pain after breast cancer surgery. This study aimed to investigate the efficacy of combined perioperative oral pregabalin and postoperative esketamine in preventing chronic pain after breast cancer surgery.
METHODS
Ninety patients undergoing elective breast cancer surgery were randomized into the combined pregabalin and esketamine group (EP group) and the general anesthesia alone group (Control group). The EP group received 150 mg of oral pregabalin 1 h before surgery and twice daily for seven days postoperatively, and a patient-controlled analgesia pump after surgery that delivered 100 μg sufentanil + 1.25 mg/kg esketamine + 4 mg tropisetron in 100 mL saline solution intravenously. The Control group received placebo capsules before and after the surgery and routine postoperative analgesia (100 μg sufentanil + 4 mg tropisetron in 100 mL saline solution). The primary outcome was the incidence of chronic pain three and six months after surgery. Secondary outcomes included acute postoperative pain, postoperative opioid consumption, and incidence of adverse events.
RESULTS
The incidence of chronic pain in the EP group was significantly lower than in the Control group three (14.3% vs 46.3%, = 0.005) and six (7.1% vs 31.7%, = 0.009) months postoperatively. The rest numerical rating scale (NRS) pain scores 1-3 days postoperatively and coughing NRS pain scores 1-7 days postoperatively in the EP group were significantly lower than in the Control group (all ˂ 0.05). The cumulative sufentanil consumption in the EP group during postoperative 0-12, 12-24, and 24-48, 0-24, and 0-48 hours were significantly lower than in the Control group (all ˂ 0.05).
CONCLUSION
Combined perioperative oral pregabalin and postoperative esketamine effectively prevented chronic pain after breast cancer surgery, improved acute postoperative pain, and reduced postoperative opioid consumption.
Topics: Humans; Female; Breast Neoplasms; Pregabalin; Analgesics, Opioid; Chronic Pain; Saline Solution; Sufentanil; Tropisetron; Pain, Postoperative
PubMed: 37313456
DOI: 10.2147/DDDT.S413273 -
Nature Nov 2018The serotonin 5-HT receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers...
The serotonin 5-HT receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression. In spite of several reported pLGIC structures, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody or without ligand. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.
Topics: Allosteric Regulation; Animals; Binding Sites; Cryoelectron Microscopy; Ion Channel Gating; Ligands; Mice; Molecular Dynamics Simulation; Movement; Protein Conformation; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Single-Domain Antibodies; Thermodynamics; Tropisetron
PubMed: 30401839
DOI: 10.1038/s41586-018-0672-3 -
Biomedicine & Pharmacotherapy =... Feb 2019The objective of the present investigation was to explore the possible effect of the 5-HT3 receptor antagonist tropisetron on the expression levels of the inflammatory...
OBJECTIVE
The objective of the present investigation was to explore the possible effect of the 5-HT3 receptor antagonist tropisetron on the expression levels of the inflammatory factors interleukin 6 (IL-6), creatine kinase isoenzyme (CK-MB), soluble growth stimulating gene 2 protein (sST2) and immunoglobulin E (IgE), as well as the cardiac action potential in septic rats.
METHODS
The cecal ligation and perforation (CLP) method was utilized to construct abdominal infarction in rats. A total of 68 male adult Sprague Dawley rats were used, including 40 for assessing survival and 28 for detecting the expression levels of IL-6 and IgE, myocardial injury, cardiac dysfunction and the cardiac action potential. These 28 rats were divided into the sham (6 rats), sham + Tropisetron (6 rats), CLP (8 rats) and CLP + Tropisetron (8 rats) groups. Twenty-four hours after establishment of the sepsis rat model, immunohistochemistry was used to analyze 5-HT3 receptor protein expression, and enzyme-linked immunosorbent assay (ELISA) was employed to monitor the serum levels of IL-6, CKMB, sST2 and IgE. Furthermore, the structure of the myocardium in various groups was examined by H&E staining.
RESULTS
The levels of IL-6, CK-MB, sST2 and IgE in the sepsis group were significantly higher than those of the sham group (P < 0.01). Furthermore, the heart rate in the sepsis group was lower than that of the sham group (P < 0.01), and the time of atrial ventricular action potential in the sepsis group was longer than that of the sham group (P < 0.05). In addition, immunohistochemical analyses showed that the area, intensity and index of 5-HT3 receptor in the sepsis group were significantly lower than those of the sham group (P < 0.01). Importantly, the 5-HT3 receptor antagonist Tropisetron exhibited significant inhibitory effects IL-6, CK-MB, sST2 and IgE expression levels, and inductive effects on atrial ventricular action potential in the sepsis group.
CONCLUSIONS
Sepsis leads to systemic inflammatory reaction, resulting in myocardial injury, structural changes and immune imbalance. The inhibitory effect of tropisetron on inflammation, and the regulatory inflammatory disorder by the efferent vagus nerve may be one of the important mechanisms leading to cardiac electrophysiological changes in sepsis.
Topics: Action Potentials; Animals; Disease Models, Animal; Heart; Inflammation; Inflammation Mediators; Isolated Heart Preparation; Male; Rats; Rats, Sprague-Dawley; Sepsis; Serotonin 5-HT3 Receptor Antagonists; Tropisetron
PubMed: 30529771
DOI: 10.1016/j.biopha.2018.11.142 -
Scientific Reports Aug 2020Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which...
Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HTR expression level while thymol treatment normalized the 5-HTR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HTR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HTR. Our study suggest that thymol improves IBS symptoms through 5-HTR, could be useful for the treatment of IBS.
Topics: Administration, Oral; Animals; Behavior, Animal; Chronic Disease; Gastrointestinal Transit; Intestine, Small; Irritable Bowel Syndrome; Male; Models, Biological; Molecular Docking Simulation; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Stress, Psychological; Thymol
PubMed: 32807797
DOI: 10.1038/s41598-020-70420-4