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Ahmad Reza Dehpour - One of the best experts on this subject based on the ideXlab platform.
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in vitro effects of Tropisetron and granisetron against echinococcus granulosus s s protoscoleces by involvement of calcineurin and calmodulin
Parasites & Vectors, 2021Co-Authors: Mohammad Reza Shiee, Eshrat Beigom Kia, Farzaneh Zahabiun, Mahmood Naderi, Elahe Motevaseli, Shahram Nekoeian, Majid Fasihi Harandi, Ahmad Reza DehpourAbstract:Cystic echinococcosis (CE) is a disease caused by the larval stage of Echinococcus granulosus sensu lato (s.l.). The treatment of CE mainly relies on the use of benzimidazoles, which can commonly cause adverse side effects. Therefore, more efficient treatment options are needed. Drug repurposing is a useful approach for advancing drug development. We have evaluated the in vitro protoscolicidal effects of Tropisetron and granisetron in E. granulosus sensu stricto (s.s.) and assessed the expression of the calcineurin (CaN) and calmodulin (CaM) genes, both of which have been linked to cellular signaling activities and thus are potentially promising targets for the development of drugs. Protoscoleces (PSC) of E. granulosus (s.s.) (genotype G1) obtained from sheep hepatic hydatid cysts were exposed to Tropisetron and granisetron at concentrations of 50, 150 and 250 µM for various periods of time up to 10 days. Cyclosporine A (CsA) and albendazole sulfoxide were used for comparison. Changes in the morphology of PSC were investigated by light microscopy and scanning electron microscopy. Gene expression was assessed using real-time PCR at the mRNA level for E. granulosus calcineurin subunit A (Eg-CaN-A), calcineurin subunit B (Eg-CaN-B) and calmodulin (Eg-CaM) after a 24-h exposure at 50 and 250 µM, respectively. At 150 and 250 µM, Tropisetron had the highest protoscolicidal effect, whereas CsA was most effective at 50 µM. Granisetron, however, was less effective than Tropisetron at all three concentrations. Examination of morphological alterations revealed that the rate at which PSC were killed increased with increasing rate of PSC evagination, as observed in PSC exposed to Tropisetron. Gene expression analysis revealed that Tropisetron at 50 μM significantly upregulated Eg-CaN-B and Eg-CaM expression while at 250 μM it significantly downregulated both Eg-CaN-B and Eg-CaM expressions; in comparison, granisetron decreased the expression of all three genes at both concentrations. Tropisetron exhibited a higher efficacy than granisetron against E. granulosus (s.s.) PSC, which is probably due to the different mechanisms of action of the two drugs. The concentration-dependent effect of Tropisetron on calcineurin gene expression might reflect its dual functions, which should stimulate future research into its mechanism of action and evaluation of its potential therapeutical effect in the treatment of CE.
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Tropisetron suppresses colitis associated cancer in a mouse model in the remission stage
International Immunopharmacology, 2016Co-Authors: Hossein Aminikhoei, Reza Rahimian, Ahmad Reza Dehpour, Shayan Amiri, Arya Hajmirzaian, Majid Momeny, Alireza Abdollahi, Seyed Mohammad Tavangar, Seyed Hamid Ghaffari, Shahram Ejtemaei MehrAbstract:Patients with inflammatory bowel disease (IBD) have a high risk for development of colitis-associated cancer (CAC). Serotonin is a neurotransmitter produced by enterochromaffin cells of the intestine. Serotonin and its receptors, mainly 5-HT3 receptor, are overexpressed in IBD and promote development of CAC through production of inflammatory cytokines. In the present study, we demonstrated the in vivo activity of Tropisetron, a 5-HT3 receptor antagonist, against experimental CAC. CAC was induced by azoxymethane (AOM)/dextran sodium sulfate (DDS) in BALB/c mice. The histopathology of colon tissue was performed. Beta-catenin and Cox-2 expression was evaluated by immunohistochemistry as well as quantitative reverse transcription-PCR (qRT-PCR). Alterations in the expression of 5-HT3 receptor and inflammatory-associated genes such as Il-1β, Tnf-α, Tlr4 and Myd88 were determined by qRT-PCR. Our results showed that tumor development in Tropisetron-treated CAC group was significantly lower than the controls. The qRT-PCR analysis demonstrated that the expression of 5-HT3 receptor was significantly increased following CAC induction. In addition, Tropisetron reduced expression of β-catenin and Cox-2 in the CAC experimental group. The levels of Il-1β, Tnf-α, Tlr4 and Myd88 were significantly decreased upon Tropisetron treatment in the AOM/DSS group. Taken together, our data show that Tropisetron inhibits development of CAC probably by attenuation of inflammatory reactions in the colitis.
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involvement of nitric oxide cyclic guanosine monophosphate pathway in the antidepressant like effect of Tropisetron and ondansetron in mice forced swimming test and tail suspension test
European Journal of Pharmacology, 2016Co-Authors: Shayan Amiri, Nastaran Kordjazy, Arya Hajmirzaian, Hossein Aminikhoei, Sattar Ostadhadi, Ahmad Reza DehpourAbstract:Antidepressant-like effects of 5-hydroxytryptamine subtype 3 (5-HT3) antagonists including Tropisetron and ondansetron have been previously demonstrated in the literature. It was reported that stimulation of 5-HT3 receptors activate the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, which is involved in regulation of behavioral and emotional functions. In our study, treating animals with Tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01 and 0.1µg/kg) significantly decreased the immobility time in forced swimming test (FST) and tail-suspension test (TST). Co-administration of subeffective doses of Tropisetron (1mg/kg) and ondansetron (0.001µg/kg) with subeffective dose of l-NAME (10mg/kg, nonselective NO synthase (NOS) inhibitor) and 7-nitroindazole (25mg/kg, neural NOS inhibitor) exerted antidepressant-like effect in FST and TST, while aminoguanidine (50mg/kg, inducible NOS inhibitor) did not enhance the antidepressant-like effect of 5-HT3 antagonists. Besides, l-arginine (750mg/kg, NO precursor) and sildenafil (5mg/kg, phosphodiesterase inhibitor) suppressed the anti-immobility effect of 5-HT3 antagonists. None of the treatments altered the locomotor behavior of mice in open-field test. Also, hippocampal (but not cortical) nitrite level was significantly lower in Tropisetron and ondansetron-treated mice compared with saline-injected mice. Also, co-administration of 7-nitroindazole with Tropisetron or ondansetron caused a significant decrease in hippocampal nitrite levels. In conclusion, we suggest that antidepressant-like effect of Tropisetron and ondansetron are partially mediated by modulation of NO-cGMP pathway.
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Tropisetron inhibits high glucose induced calcineurin nfat hypertrophic pathway in h9c2 myocardial cells
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Firouzeh Asadi, Ahmad Reza Dehpour, Ali Razmi, Massoumeh ShafieiAbstract:Objectives Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of Tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism. Methods H9c2 myocardial cells were treated with Tropisetron or cyclosporine A 1 h before exposure to HG for 48 h. Key findings Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca2+ level, calcineurin expression and nuclear translocation of NFATc4. Both Tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca2+ was not affected. Conclusion Our results showed that Tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway.
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Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function
Biochimica et Biophysica Acta, 2015Co-Authors: Shayan Amiri, Shahram Ejtemaei Mehr, Ahmad Reza Dehpour, Arya Hajmirzaian, Hossein Aminikhoei, Maryam Rahimibalaei, Parvaneh Naserzadeh, Mirjamal HosseiniAbstract:Abstract Background Early social isolation stress (SIS) is associated with the occurrence of anxiety behaviors. It seems interaction between the nitrergic system and mitochondrial function plays a role in mediating the anxiety-like behaviors. In this study, we aimed to investigate the anxiolytic effects of Tropisetron in animal model of SIS and we try to illustrate the possible role of nitrergic system and mitochondrial function. Methods We applied early social isolation paradigm to male NMRI mice. Animals treated with various doses of Tropisetron, nitric oxide agents or their combination and anxiety-like behaviors of animals were assessed using valid behavioral tests including elevated plus maze (EPM), open-field test (OFT) and hole-board test (HBT) in their adulthood. Effects of housing conditions and drug treatments on the mitochondrial function were investigated in the hippocampus by assessing the ATP, GSH, ROS and nitrite levels. Results Anxiogenic effects of early SIS were assessed in the EPM, OFT, and HBT. Also, SIS disrupted mitochondrial function and caused oxidative stress in the hippocampus of stressed animals. Tropisetron showed an anxiolytic effect in the stressed mice. Also, these effects were mediated by nitrergic system by affecting mitochondrial function and modulating the oxidative stress. L-arginine, a nitric oxide precursor, abolished the anxiolytic effects of Tropisetron in the behavioral tasks and blocked the protective effects of it against mitochondrial and oxidative challenge. Conclusions and general significance Our results demonstrated Tropisetron attenuated the anxiogenic effects of SIS by mitigation of the negative effects of nitric oxide on mitochondrial function.
Massoumeh Shafiei - One of the best experts on this subject based on the ideXlab platform.
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Tropisetron inhibits high glucose induced calcineurin nfat hypertrophic pathway in h9c2 myocardial cells
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Firouzeh Asadi, Ahmad Reza Dehpour, Ali Razmi, Massoumeh ShafieiAbstract:Objectives Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of Tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism. Methods H9c2 myocardial cells were treated with Tropisetron or cyclosporine A 1 h before exposure to HG for 48 h. Key findings Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca2+ level, calcineurin expression and nuclear translocation of NFATc4. Both Tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca2+ was not affected. Conclusion Our results showed that Tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway.
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inhibition of calcineurin nfat pathway plays an essential role in renoprotective effect of Tropisetron in early stage of diabetic nephropathy
European Journal of Pharmacology, 2015Co-Authors: Anita Barzegarfallah, Ahmad Reza Dehpour, Houman Alimoradi, Mojgan Asgari, Ali Razmi, Massoumeh ShafieiAbstract:Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether Tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with Tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats. In conclusion, our results showed that Tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of Tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue.
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Tropisetron ameliorates early diabetic nephropathy in streptozotocin induced diabetic rats
Clinical and Experimental Pharmacology and Physiology, 2015Co-Authors: Anita Barzegarfallah, Ahmad Reza Dehpour, Houman Alimoradi, Firouzeh Asadi, Mojgan Asgari, Massoumeh ShafieiAbstract:It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that Tropisetron exerts anti-inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of Tropisetron on early diabetic nephropathy in streptozotocin-induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with Tropisetron (3 mg/kg); (iv) normal rats treated with Tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor-I± were also determined. Streptozotocin-treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor-I±, and urinary albumin excretion. Both granisetron and Tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with Tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor-I±, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that Tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti-oxidative and anti-inflammatory mechanisms that appear to be independent of the 5-HT3 receptor. © 2015 Wiley Publishing Asia Pty Ltd.
Bernd L Fiebich - One of the best experts on this subject based on the ideXlab platform.
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Tropisetron suppresses collagen synthesis in skin fibroblasts via α7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model
Arthritis & Rheumatism, 2013Co-Authors: Agatha Stegemann, Anca Sindrilaru, Beate Eckes, Adriana Del Rey, Alexander Heinick, Jan S Schulte, Frank U Muller, Sergei A Grando, Bernd L Fiebich, Karin ScharffetterkochanekAbstract:Objective There is increasing evidence that serotonin (5-hydroxytryptamine [5-HT]) and distinct 5-HT receptors are involved in the pathogenesis of systemic sclerosis. The aim of this study was to test the hypothesis that Tropisetron, a routinely used antiemetic agent previously characterized as a 5-HT3/4 receptor–modulating agent, can directly affect collagen synthesis in vitro and attenuate experimentally induced fibrosis in vivo. Methods Functional in vitro studies were performed using human dermal fibroblasts (HDFs). Signal transduction studies included immunofluorescence analysis, Western immunoblotting, promoter reporter assays, cAMP/Ca2+ measurements, and use of pharmacologic activators and inhibitors. Gene silencing was performed using small interfering RNA. Putative receptors of Tropisetron were detected by semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) and immunofluorescence. The murine model of bleomycin-induced scleroderma was used to assess the antifibrogenic and antifibrotic effects of Tropisetron in vivo. Collagen expression in vitro, ex vivo, and in situ was determined by real-time RT-PCR analysis, Western immunoblotting, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and immunohistochemical analysis. Results Tropisetron suppressed collagen synthesis induced by transforming growth factor β1 (TGFβ1). This effect was independent of 5-HT3/4 receptor but was mediated via α7 nicotinic acetylcholine receptor (α7nAChR). Suppression of TGFβ1-induced collagen synthesis occurred via an unknown molecular mechanism not involving modulation of the Smad, cAMP, Akt, c-Jun, or MAPK pathway. In vivo, Tropisetron not only prevented skin fibrosis but also reduced the collagen content in established dermal fibrosis induced by bleomycin. Conclusion Tropisetron directly reduces collagen synthesis in HDFs via an α7nAChR-dependent mechanism. The antifibrogenic and antifibrotic effects of this agent observed in a mouse model of bleomycin- induced scleroderma indicate the future potential of Tropisetron in the treatment of fibrotic diseases such as scleroderma.
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the anti inflammatory effects of the 5 ht3 receptor antagonist Tropisetron are mediated by the inhibition of p38 mapk activation in primary human monocytes
Brain Behavior and Immunity, 2013Co-Authors: Christian Stratz, Eduardo Munoz, Harsharan S Bhatia, Ravi Shankar Akundi, Thomas Nuhrenberg, Dietmar Trenk, Bernd L FiebichAbstract:There is evidence from human and animal research that 5-hydroxytryptamine (5-HT) 3 receptor antagonists, particularly Tropisetron, exert analgesic and anti-inflammatory activity. We have demonstrated that Tropisetron inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha and interleukin-(IL-)1beta release in primary human monocytes. The underlying mechanisms of these effects have not been investigated in detail so far. The molecular mechanisms of the anti-inflammatory effects of Tropisetron were investigated in human primary monocytes in vitro by studying IL-1beta and TNF-α mRNA levels by PCR and reporter gene assay and by elucidating the phosphorylation of p38 mitogen activated kinase (MAPK) by Western blot. The steady state levels of IL-1beta and TNF-α mRNA in LPS-activated human peripheral monocytes and the transcriptional activity of the TNF-α promoter were not inhibited by Tropisetron, suggesting that the inhibitory activity of this 5-HT3 receptor antagonist takes place at the post-transcriptional level. Additionally, we found that Tropisetron prevents the phosphorylation and thus activation of the p38 MAPK, which is involved in post-transcriptional regulation of various cytokines. Our data indicate that the anti-inflammatory effects of the 5-HT3 receptor antagonist Tropisetron, as shown in vivo, are possibly mediated by a selective inhibition of pro-inflammatory cytokines at the post-transcriptional level. 5-HT3 receptor antagonists are therefore a new and promising therapeutic option. New and more selective – in respect to the 5-HT3 subtypes – 5-HT3R antagonists might be a future perspective in the pharmacological treatment of inflammatory diseases.
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the anti inflammatory effects of the 5 ht3 receptor antagonist Tropisetron are mediated by the inhibition of p38 mapk activation in primary human monocytes
International Immunopharmacology, 2012Co-Authors: Christian Stratz, Eduardo Munoz, Harsharan S Bhatia, Ravi Shankar Akundi, Thomas Nuhrenberg, Dietmar Trenk, Bernd L FiebichAbstract:Abstract Background There is evidence from human and animal research that 5-hydroxytryptamine (5-HT) 3 receptor antagonists, particularly Tropisetron, exert analgesic and anti-inflammatory activity. We have demonstrated that Tropisetron inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)alpha and interleukin-(IL-)1beta release in primary human monocytes. The underlying mechanisms of these effects have not been investigated in detail so far. Methods The molecular mechanisms of the anti-inflammatory effects of Tropisetron were investigated in human primary monocytes in vitro by studying IL-1beta and TNFalpha mRNA levels by PCR and reporter gene assay and by elucidating the phosphorylation of p38 mitogen activated kinase (MAPK) by Western blot. Results The steady state levels of IL-1beta and TNFalpha mRNA in LPS-activated human peripheral monocytes and the transcriptional activity of the TNFalpha promoter were not inhibited by Tropisetron, suggesting that the inhibitory activity of this 5-HT 3 receptor antagonist takes place at the post-transcriptional level. Additionally, we found that Tropisetron prevents the phosphorylation and thus activation of the p38 MAPK, which is involved in post-transcriptional regulation of various cytokines. Conclusion Our data indicate that the anti-inflammatory effects of the 5-HT 3 receptor antagonist Tropisetron, as shown in vivo , are possibly mediated by a selective inhibition of pro-inflammatory cytokines at the post-transcriptional level. 5-HT 3 receptor antagonists are therefore a new and promising therapeutic option. New and more selective – in respect to the 5-HT 3 subtypes – 5-HT 3 R antagonists might be a future perspective in the pharmacological treatment of inflammatory diseases.
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the 5 ht3 receptor antagonist Tropisetron inhibits t cell activation by targeting the calcineurin pathway
Biochemical Pharmacology, 2005Co-Authors: Laureano De La Vega, Eduardo Munoz, Marco A Calzado, Klaus Lieb, Eduardo Candelariojalil, Harald Gschaidmeir, Lothar Farber, Wolfgang Mueller, Thomas Stratz, Bernd L FiebichAbstract:Tropisetron, an antagonist of serotonin type 3 receptor, has been investigated in chronic inflammatory joint process. Since T cells play a key role in the onset of several inflammatory diseases, we have evaluated the immunosuppressive activity of Tropisetron in human T cells, discovering that this compound is a potent inhibitor of early and late events in TCR-mediated T cell activation. Moreover, we found that Tropisetron specifically inhibited both IL-2 gene transcription and IL-2 synthesis in stimulated T cells. To further characterize the inhibitory mechanisms of Tropisetron at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-(kappa)B, NFAT and AP-1 transcription factors in Jurkat T cells. We found that Tropisetron inhibited both the binding to DNA and the transcriptional activity of NFAT and AP-1. We also observed that Tropisetron is a potent inhibitor of PMA plus ionomycin-induced NF-(kappa)B activation but in contrast TNF(alpha)-mediated NF-(kappa)B activation was not affected by this antagonist. Finally, overexpression of a constitutively active form of calcineurin indicated that this phosphatase may represent one of the main targets for the inhibitory activity of Tropisetron. These findings provide new mechanistic insights into the anti-inflammatory activities of Tropisetron, which are probably independent of serotonin receptor signalling and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.
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Tropisetron inhibits serotonin induced pge2 release from macrophage like synovial cells in serum free tissue culture
Scandinavian Journal of Rheumatology, 2004Co-Authors: Matthias F Seidel, Bernd L Fiebich, Eduardo Candelariojalil, Gudrun Ulrichmerzenich, Franzwalter Koch, H VetterAbstract:Tropisetron has shown potent analgesic and antiphlogistic effects in patients with rheumatic diseases such as osteoarthritis (1) or tendinopathies (2). These observations suggest that serotonin (5-HT) plays an important role in pain and inflammation. Objectives: The objective of our study was to determine if 5-HT stimulates the release of further inflammatory mediators such as prostaglandin E2 (PGE2) and if this effect can be blocked by Tropisetron. To resolve these questions, we used a novel serum-free tissue culture technique for dissociated synovial tissue (3). This method permits in vitro experiments without perturbation by serum factors. Our cultures are characterized by 80% synoviocytes expressing the macrophage-specific marker CD68. Methods: Dissociated synovial tissue from osteoarthritis patients (n~5, mean age 67.2i6.2 years) was cultured for 11 days in Iscove’s Modified Dulbecco’s Eagle Medium supplemented with insulin. Cultures were then stimulated with 10, 10, and 10 M 5-HT and antagonized with 50 mg/mL Tropisetron. Positive controls consisted of stimulation with 100 U/ml interleukin 1b (IL-1b). Negative controls included unstimulated cells or co-culture with Tropisetron alone. After 48 h, PGE2 levels were determined using a conventional enzymeimmunoassay (EIA). PGE2 concentrations/mg protein were expressed as percent of controls and compared using the Mann-Whitney rank sum test. In addition, RT-PCR analyses for 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3, and 5-HT4 receptor subtypes (4) were performed using synovial tissue (n~5). Results: The results (Figure 1) showed an increase of PGE2 in response to 10 25 M 5-HT by 421.8i84.9% (meanistandard error, p~v0.0001), whereas 10 and 10 M did not show significant effects (126.9i28.7%; p~0.37 and 96.8i28.7%; p~0.87, respectively). Stimulation by IL-1b caused an increase of 1347.5i481.4% (p~0.0094). Preincubation with Tropisetron completely suppressed the serotonin-induced PGE2 release. RT-PCR showed an expression of the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 but not 5-HT4 receptor subtype. Conclusions: The increase of PGE2 shows that serotonin is a potent proinflammatory mediator. The findings indicate the presence of 5-HT3 receptors and a Tropisetron-induced suppression of this response. Additional analyses are necessary to further elucidate the underlying inflammatory mechanisms and inhibitory effect of Tropisetron.
Benhong Zhou - One of the best experts on this subject based on the ideXlab platform.
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compatibility and stability of dezocine and Tropisetron in 0 9 sodium chloride injection for patient controlled analgesia administration
Medicine, 2018Co-Authors: Peng Chen, Fuchao Chen, Benhong ZhouAbstract:Tropisetron is an adjuvant for dezocine used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the institutional incidence of postoperative nausea and vomiting (PONV), which decreases resource utilization and cost. However, no scientific evidence has been reported in the literature demonstrating analytical confirmation of the compatibility and stability of the combination of dezocine and Tropisetron. Thus, the present study aimed to investigate the stability of dezocine with Tropisetron in 0.9% sodium chloride injection form for PCA administration. Commercial solutions of dezocine and Tropisetron were combined and examined for compatibility and stability when diluted with 0.9% sodium chloride injection in polyolefin bags and glass bottles stored at 4°C or 25°C for up to 14 days. The initial concentrations were 40 mg/100 mL dezocine and 5 mg/100 mL Tropisetron. For all samples, the compatibility parameters (including precipitation, cloudiness, discoloration, and pH values) were evaluated. Chemical stability was also determined using high-performance liquid chromatographic (HPLC) analysis. After a 14-day period of storage at 4°C or 25°C, the initial concentrations of dezocine and Tropisetron were maintained at at least 98%. All of the mixtures remained clear and colorless throughout the observation period, and no color change or precipitation was observed. These results indicated that admixtures of 40 mg/100 mL dezocine and 5 mg/100 mL Tropisetron in 0.9% sodium chloride injection were stable for at least 14 days when stored in polyolefin bags or glass bottles at 4°C or 25°C and protected from light.
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stability of butorphanol Tropisetron mixtures in 0 9 sodium chloride injection for patient controlled analgesia use
Medicine, 2015Co-Authors: Fuchao Chen, Xiaoya Shi, Jinguo Yang, Benhong ZhouAbstract:Tropisetron is an adjuvant for butorphanol used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the incidence of postoperative nausea and vomiting. However, this admixture is not available commercially and stability data applicable to hospital practice are limited. This study aimed to describe the drug compounding and evaluates the long-term (up to 14 days) stability of butorphanol and Tropisetron in 0.9% sodium chloride injection for PCA use. In this study, commercial solutions of butorphanol tartrate and Tropisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and Tropisetron hydrochloride 0.05 mg/mL. The polyolefin bags and glass bottles were stored at 4°C and 25°C for up to 14 days. The drug stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography assay of drug concentrations. The data obtained for admixtures prepared and stored at temperatures of 25°C and 4°C show the drugs have maintained at least 98% of the initial concentration. All solutions remained clear and colorless over the 14-day period, and the pH value did not change significantly. The results indicate that admixtures of butorphanol tartrate 0.08 mg/mL and Tropisetron hydrochloride 0.05 mg/mL in 0.9% sodium chloride injection solution were stable for 14 days when stored in polyolefin bags or glass bottles at 4°C and 25°C and protected from light. The infusion is feasible for manufacturing in pharmacy aseptic units and can be stored for up to 14 days for routine use in PCA infusions.
Ali Razmi - One of the best experts on this subject based on the ideXlab platform.
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Tropisetron inhibits high glucose induced calcineurin nfat hypertrophic pathway in h9c2 myocardial cells
Journal of Pharmacy and Pharmacology, 2016Co-Authors: Firouzeh Asadi, Ahmad Reza Dehpour, Ali Razmi, Massoumeh ShafieiAbstract:Objectives Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of Tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism. Methods H9c2 myocardial cells were treated with Tropisetron or cyclosporine A 1 h before exposure to HG for 48 h. Key findings Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca2+ level, calcineurin expression and nuclear translocation of NFATc4. Both Tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca2+ was not affected. Conclusion Our results showed that Tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway.
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inhibition of calcineurin nfat pathway plays an essential role in renoprotective effect of Tropisetron in early stage of diabetic nephropathy
European Journal of Pharmacology, 2015Co-Authors: Anita Barzegarfallah, Ahmad Reza Dehpour, Houman Alimoradi, Mojgan Asgari, Ali Razmi, Massoumeh ShafieiAbstract:Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether Tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with Tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats. In conclusion, our results showed that Tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of Tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue.
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Tropisetron attenuates cisplatin induced nephrotoxicity in mice
European Journal of Pharmacology, 2014Co-Authors: Mohammad Reza Zirak, Reza Rahimian, Shahram Ejtemaei Mehr, Kazem Mousavizadeh, Mahmoud Ghazikhansari, Ata Abbasi, Ali Razmi, Ahmad Reza DehpourAbstract:Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by Tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (Tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of Tropisetron, we concluded that this effect of Tropisetron is not mediated by α7nAChR.Our results showed that Tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.
