Tropisetron attenuates high glucose-induced oxidative stress and inflammation in ARPE-19 cells in vitro via regulating SIRT1/ROCK1 signaling.

Diabetic retinopathy (DR) is the leading cause of acquired blindness in diabetic patients. Tropisetron (TRO) exerts potent therapeutic effects against diabetic tissues. The present study aimed to investigate the effects of TRO on retinal injury under diabetic condition. Human retinal pigment epithelial cell line ARPE-19 was treated with high glucose (HG) for 48 h to mimic hyperglycemia-induced retinal damage and subsequently treated with multiple concentrations of TRO for therapeutic intervention. Cell viability and lactate dehydrogenase (LDH) release were detected to assess cell damage. The production of inflammatory cytokines and oxidative stress-related factors was evaluated by corresponding commercial kits. Cell apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of inflammation-, apoptosis-, and SIRT1/ROCK1-related proteins was examined using western blot analysis. Additionally, ARPE-19 cells were transfected with over-express ROCK1 (Ov-ROCK1) or pretreatment with SIRT1 inhibitor EX527 to perform the rescue experiments. TRO alleviated cell damage in HG-induced ARPE-19 cells through elevating cell viability and reducing LDH release. HG-caused excessive production of TNF-α, IL-1ß and IL-6, ROS, malondialdehyde and decreased superoxide dismutase activity were partly inhibited by TRO treatment. HG-induced cell apoptosis, accompanied with the upregulation of proapoptotic proteins and the downregulation of antiapoptotic proteins, was hindered by TRO treatment. HG led to the loss of SIRT1 and an elevation of ROCK1 in ARPE-19 cells, which was reversed following TRO treatment. Furthermore, pretreatment with EX527 or transfected with Ov-ROCK1 partially abolished the protective role of TRO against inflammation, oxidative stress and cell apoptosis in HG-challenged ARPE-19 cells. TRO exerted a protective role against HG-caused ARPE-19 cells inflammation, oxidative stress and cell apoptosis by regulating SIRT1/ROCK1 axis, suggesting that TRO might be therapeutic agent for alleviating retinal pigment epithelial cell damage in DR.

Tropisetron improved testicular inflammation in the streptozotocin-induced diabetic rats: The role of toll-like receptor 4 (TLR4) and mir146a.

As a serotonin antagonist, tropisetron positively affects blood glucose lowering, insulin synthesis, pancreas inflammation, and apoptosis in diabetes. Reproductive disorders are one of the diabetes-induced chronic complications. The present study aimed to evaluate the effect of tropisetron on diabetes-induced testicular inflammation, its signaling pathway, and mir146a. To this end, animals were assigned to the control, tropisetron, diabetes (DM), DM-tropisetron, and DM-glibenclamide groups. Streptozotocin (50 mg/kg) was intraperitoneally injected to provide diabetes. Tropisetron and glibenclamide were then administrated intraperitoneally for 2 weeks after diabetes induction. Testes histology, real-time polymerase chain reaction, western blot analysis, ELISA, and immunohistochemistry assays were also performed. The finding revealed that tropisetron significantly improved diabetes-induced testis damages, lowered TLR4, TRAF6, IRAK1, NF-κB, and caspase3 protein expressions, and decreased TNF-α and IL-1 levels. Moreover, the mir146a expression declined following the tropisetron treatment. This study demonstrated that the significant role of tropisetron in lowering testicular inflammation and apoptosis might have been due to the inhibition of the TLR4/IRAK1/TRAF6 signaling pathway and thereby the attenuation of NF-κB and caspase3 expression and inflammatory cytokines. Furthermore, the downregulation of mir146a, as an inflammatory microRNA interacting with TLR4, showed another pathway, through which tropisetron improved diabetes-induced testicular injuries.

Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload-induced cardiac hypertrophy model.

Tropisetron exerts a protective effect against cardiac complications, particularly cardiac hypertrophy. Oxidative stress and apoptosis are the main contributors to the pathogenesis of cardiac hypertrophy. Sirtuins, a family of histone deacetylases, are connected to cellular oxidative stress signaling and antioxidant defense. Sirtuins are also linked to apoptosis which is an important mechanism in the progression of cardiac hypertrophy to heart failure. Literature also suggests that tropisetron impedes apoptosis, partly mediated through an antioxidant mechanism. Therefore, we examined if tropisetron fights cardiac hypertrophy by adjusting sirtuin family proteins (Sirts) and components of mitochondrial death pathway, Bcl-associated X (BAX), Bcl-2-associated death promoter (BAD). Male Sprague-Dawley rats got divided into four groups, including control (Ctl), tropisetron (Trop), cardiac hypertrophy (Hyp), and hypertrophic rats under tropisetron treatment (Hyp + Trop). Pathological cardiac hypertrophy was induced by surgical abdominal aortic constriction (AAC). The increased expression of brain natriuretic peptide (BNP) in the Hyp group confirms the cardiac hypertrophy establishment. The mRNA levels of SIRT1, SIRT3, SIRT7, and BAD also upregulated in the hypertrophic group (p < 0.001). Postoperational administration of tropisetron for 3 weeks lowered the increased expression of BNP (p < 0.05) and BAD (p < 0.001), though the reduction of BAX expression was statistically insignificant (p > 0.05). Tropisetron treatment also restored the normal level of SIRT1/3/7 genes expression in the Hyp + Trop group (p < 0.05). Present findings suggest that tropisetron can suppress cardiomyocyte hypertrophy progression to heart failure by counteracting BNP, SIRT1, SIRT3, Sirt7, and BAD overexpression-mediated apoptosis in a rat model of cardiac hypertrophy.

Prevention of postoperative nausea and vomiting after gynaecological day surgery under remimazolam general anesthesia: a randomized double-blind controlled study.

PURPOSE: To observe the effect of different antiemetic drugs for the prevention of postoperative nausea and vomiting (PONV) after gynaecological day surgery under remimazolam general anesthesia. METHODS: One hundred ninety-two patients were selected for gynaecological day surgery and randomly divided into three groups: droperidol group (DD group), tropisetron group (DT group) and control group (DC group). Flurbiprofen axetil 50 mg and dexamethasone 5 mg were given intravenously before induction of anesthesia, and 2 min later droperidol 1 mg was given intravenously to the DD group, tropisetron 5 mg to the DT group and saline (5 ml) to the DC group. Induction of anesthesia: remimazolam 6 mg/kg/h was continuously infused until sleep, mivacurium 0.2 mg/kg and alfentanil 20ug/kg were slowly pushed, 3 min later intubation was performed to control breathing. Maintenance of anesthesia: 40ug/kg/h of alfentanil, 1 mg/kg/h of remimazolam continuous infusion. After awakening and extubation, the patient was transferred to the PACU. PONV were recorded in the PACU and an electronic questionnaire was pushed 24 h after surgery. RESULTS: The incidence of PONV within the PACU was significantly lower in the DD (14.5%)and DT(26.7%) groups than in the DC(50%) group (p < 0.01), there was no significantly difference between the DT and DD groups. There were no significant difference in the incidence of PONV in 24 h after surgery between the three groups(DD:DT:DC = 44.5%:45.1%:63.8%,p > 0.05). CONCLUSIONS: Droperidol or tropisetron combined with dexamethasone is superior to dexamethasone alone for the prevention of PONV in the PACU after remimazolam combined with alfentanil anesthesia, with no significant difference in the incidence of PONV in 24 h after surgery.

[Application of Methylprednisolone Sodium Succinate Combined with Tropisetron in Prevention of Nausea and Vomiting under Microvascular Decompression of Hemifacial Spasm].

Objective To evaluate the effect of methylprednisolone sodium succinate combined with tropisetron on postoperative nausea and vomiting(PONV)under microvascular decompression of hemifacial spasm.Methods From January to June 2019,485 patients undergoing microvascular decompression for facial spasm at Department of Neurosurgery,Peking University People's Hospital were randomly assigned into two groups with random number table method.For group A(n=242),2 ml saline was administrated by intravenous drip before induction and 5 mg tropisetron after operation.For group B(n=243),40 mg methylprednisolone sodium succinate was administrated by intravenous drip before induction and 5 mg tropisetron after operation.The anesthesia time,operation time,and incidence of PONV in 0-24 h and 24-48 h were recorded for the comparison of the remedial treatment rate of nausea and vomiting between the two groups.Results There was no significant difference in age,gender,smoking history,body mass index value,American Society of Anesthesiologists score,medical history,surgical side,PONV history,operation time or anesthesia time between the two groups(all P > 0.05).The incidence of PONV in group A was 35.5% and 18.2% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(18.5%,χ 2=7.331,P=0.007;8.2%,χ 2=4.364,P=0.037)in group B.The application rate of antiemetic drugs in group A was 15.2% and 8.7% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(5.3%,χ 2=5.327,P=0.021;2.0%,χ 2=4.432,P=0.035)in group B.Conclusion The combination of methylprednisolone sodium succinate and tropisetron can effectively prevent PONV under microvascular decompression of hemifacial spasm,with the performance superior to single drug treatment.

Tropisetron attenuates tumor growth and progression in an experimental model of mouse lung cancer.

The antineoplastic effects of 5-hydroxytryptamine (5-HT) receptor antagonists have been shown in previous studies. However, the exact underlying mechanisms mediating these antineoplastic effects are unclear. In the present study, we assessed the antineoplastic effects of tropisetron, a 5-HT receptor antagonist, in an experimental model of lung cancer in BALB/c mouse. Lewis lung carcinoma cell line was used to induce lung cancer. Mice were divided into four groups (n = 6) as follows: tumor-bearing mice + tropisetron (5 mg/kg intraperitoneally [IP]), tumor-bearing mice + tropisetron (10 mg/kg IP), tumor-bearing mice + saline, healthy mice + tropisetron (10 mg/kg). Tumor burden, interferon-γ (IFN-γ), interleukin (IL)-4, pathological response, Ki-67, and E-cadherin were assessed using enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Comet assay was used to assess DNA toxicity. Tropisetrone-treated animals (either 5 or 10 mg/kg) showed significantly lower tumor sizes at the day 24th after tumor induction. Tropisetron received animals also showed significantly higher levels of IFN-γ, E-cadherin, pathologic response, and necrotic cells compared to the saline-treated counterparts. In addition, the levels of IL-4, and Ki-67 were significantly lower in tropisetrone treated mice in comparison with control. Furthermore, tropisteron coadministration signifcantly reduced H2 O2 -induced DNA toxicity while treatment with tropisteron alone showed no adverse effect on DNA. Tropisetrone can be used as a potential antineoplastic drug in lung cancer. This agent can promote its antineoplastic effects in part through modulating inflammatory and proliferating markers.

Tropisetron But Not Granisetron Ameliorates Spatial Memory Impairment Induced by Chronic Cerebral Hypoperfusion.

Tropisetron and Granisetorn are 5-HT3 antagonists with antiemetic effects. Tropisetron also has a partial agonistic effect on alpha-7 nicotinic acetylcholine receptors (α7 nAChRs). On the other hand, chronic cerebral hypoperfusion (CCH) attenuates cerebral blood flow and impairs cognitive functions. The goal of this study was to investigate the effect of Tropisetron and Granisetron on CCH-induced spatial memory impairment in rats. Forty-eight male Wistar rats were used in this study. 2-VO surgery was done to induce CCH and Radial Eight Arm Maz apparatus was used to evaluate spatial memory (working and reference memory). Tropisetron was injected intraperitoneally at the doses of 1 and 5 mg/kg, and Granisetron was injected intraperitoneally at the dose of 3 mg/kg. Dorsal hippocampal (CA1) neurons count, Interleukin 6 (IL-6) serum level, and serotonin-reuptake transporter (SERT) gene expression were also evaluated. The results showed, CCH impaired working and reference memory, increased IL-6 serum level, and decreased CA1 neurons and SERT expression. Tropisetron at the dose of 5 mg/kg restored all the effects of CCH. However, Granisetron did not restore CCH-induced memory impairment. Furthermore, Granisetron had no effect on IL-6. While, it increased SERT expression and CA1 neurons. In conclusion, Tropisetron but not Granisetron, ameliorated spatial memory impairment induced by CCH. We suggested conducting more detailed studies investigating the role of serotonergic system (5-HT3 receptors and serotonin transporters) and also α7 nAChRs in the effects of Tropisetron.

Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking.

BACKGROUND: The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT3 receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing. METHODS: Rats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task. RESULTS: The rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration. CONCLUSIONS: These results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT3/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking.

Comparison of ondansetron, tropisetron, and palonosetron for the prevention of postoperative nausea and vomiting after middle ear surgery.

BACKGROUND: Postoperative nausea and vomiting (PONV) are 2 of the most frequent adverse effects of anesthesia. PONV prolongs hospital stays and also delays the recovery of patients. OBJECTIVE: In this study, the effects of ondansetron, tropisetron, and palonosetron on PONV in patients who had undergone middle ear surgeries such as mastoidectomy or tympanoplasty were compared. METHODS: The study included 165 American Society of Anesthesiologists grade 1 and 2 patients aged 18 to 65 years. Patients were randomized into 3 groups by a closed envelope method. Neither the patients nor the nurses administering the treatments knew which patient belonged to which group. The anesthetic technique was standardized for all groups. During skin closure, 0.075 mg palonosetron, 5 mg tropisetron, and 8 mg ondansetron were administered intravenously to the palonosetron, tropisetron, and ondansetron groups, respectively. After completion of the surgery, the patients were followed for 48 hours. Diclofenac sodium (100 mg IM) was administered to patients experiencing pain and metoclopramide chloride (10 mg IM) was administered to patients with nausea or vomiting. Potential side effects such as headache and constipation were recorded in the postanesthesia care unit and ear, nose, and throat clinic. RESULTS: There was no significant difference in the effects of all 3 antiemetic agents on the severity of PONV (P = 0.081). At 48 hours postoperatively, the incidence of PONV was significantly lower in the palonosteron group (38.2%) than the ondansetron group (63.6%) and tropisetron group (61.8%) (P = 0.011). At 48 hours postoperatively, the incidence of postoperative nausea was significantly lower in the palonosetron group (32.7%) than in the ondansetron group (63.6%) and the tropisetron group (56.4%) (P = .003). The incidence of PONV between hours 12 and 24 postoperatively was significantly higher in the ondansetron group (27.3%) than in the palonosetron group (9.1%) (P = 0.013). The antiemetic requirement in the first hour after surgery was significantly higher in the tropisetron group (25.5%) than in the palonosetron group (7.3%) (P = .019). CONCLUSIONS: The results of the current study support those of earlier studies that suggest that palonosetron was statistically more effective than the other 2 formulations in the prevention of PONV in patients who have undergone middle ear surgery. (Curr Ther Res Clin Exp. 2019; 80:XXXXXX).

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.

Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and ß glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1ß glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.

Protective effect of tropisetron on high glucose induced apoptosis and oxidative stress in PC12 cells: roles of JNK, P38 MAPKs, and mitochondria pathway.

Tropisetron, a selective 5-HT3 receptor (5-HT3R) antagonist, is widely used to counteract chemotherapy-induced emesis. There is growing interest concerning the beneficial effects of tropisetron on the treatment of several diseases. This study was carried out to examine effects of tropisetron on high glucose (HG) induced apoptosis in PC12 cells as a suitable culture model for studying neuronal functions. Apoptosis was induced by HG, and cells were treated with HG in the absence and presence of tropisetron for varying periods of time. The viability of PC12 cells was measured by MTT assay. The ROS (reactive oxygen species) production, lipid peroxidation (LPO) levels and total antioxidant power (TAP) were measured. The expressions of proapoptotic Bax, antiapoptotic Bcl-2, caspase-3, total and phosphorylated JNK and P38 MAPKs were also examined by western blotting. The results indicated that pretreatment with tropisetron significantly improved the viability of the cells and protected PC12 cells against HG induced apoptotic cell death. It could increase the concentrations of TAP. HG induced ROS generation, Bax expression and caspase 3 activation, were prevented by tropisetron. HG also induced activation of JNK and P38 MAPKs. The phosphorylation of these kinases was inhibited by tropisetron. It may be concluded that tropisetron treatment protects PC12 cells against HG-induced apoptosis by preventing JNK, P38 activation and mitochondrial pathway.

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation.

OBJECTIVE: The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience. METHODS: TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 22-level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y1), vesicle size (Y2), polydispersity index (Y3), and zeta potential (Y4) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug-excipient interactions, and vesicle stability were also investigated. RESULTS: The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p < 0.01). The ethosomal vesicles were unilamellar with a nearly spherical shape. EPC-based ethosomes proved good stability. CONCLUSION: The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.

Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function.

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.

Involvement of PPARγ in the protective action of tropisetron in an experimental model of ulcerative colitis.

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal (GI) tract. Tropisetron, a selective 5-HT3 receptor antagonist, is highly used to counteract chemotherapy-induced emesis. Previous studies revealed the anti-inflammatory properties of this drug. The aim of this study was to evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) receptor in the protective effect of tropisetron in an animal model of ulcerative colitis. Experimental colitis was induced by a single intra-colonic instillation of 4% (V/V) acetic acid in male rats. Tropisetron (3 mg/kg) and GW9662 (PPARγ antagonist) (5 mg/kg) were given twice daily for 2 days after colitis induction. Forty-eight hours after induction of colitis, colon was removed and macroscopic and microscopic features were given. Moreover, colonic concentrations of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) levels, myeloperoxidase (MPO), and PPARγ activity were assessed. Both macroscopic and histopathological features of colonic injury were markedly ameliorated by tropisetron. Likewise, levels of NO, MDA, TNF-α, and IL-1ß diminished significantly (p < .05). GW9662 reversed the effect of tropisetron on these markers partially or completely. In addition, tropisetron increased the PPARγ and decreased the MPO activity (p < .05). Tropisetron exerts notable anti-inflammatory effects in acetic acid-induced colitis in rats, which is probably mediated through PPARγ receptors.

Dexamethasone alone vs in combination with transcutaneous electrical acupoint stimulation or tropisetron for prevention of postoperative nausea and vomiting in gynaecological patients undergoing laparoscopic surgery.

BACKGROUND: Postoperative nausea and vomiting (PONV) is commonly reported after surgery and anaesthesia. We compared the effects of combinations of electrical acupoint stimulation or tropisetron with dexamethasone with the effects of dexamethasone alone, for inhibition of PONV in gynaecological patients undergoing laparoscopic surgery. METHODS: We randomized 157 patients undergoing elective gynaecological laparoscopic surgery under general anaesthesia into the following three groups: acupoint stimulation+dexamethasone (Group Acu, n=53), tropisetron+dexamethasone (Group Trp, n=53), and dexamethasone alone (Group Dxm, n=51). The incidence of nausea, vomiting, and need for rescue antiemetics was recorded 2, 6, 24, and 48 h after surgery. RESULTS: We found significant differences in the incidence of PONV during 24 h after surgery between the combination therapy groups and the dexamethasone-alone group (P=0.021). In the first 24 h, 28% of patients in Group Acu, 26% of patients in Group Trp, and 50% of patients in Group Dxm experienced nausea, vomiting, or both. The incidence of 24 h PONV in Group Acu was significantly lower than that in Group Dxm (P=0.048; odds ratio 0.389; 95% CI 0.170-0.891). The incidence of 24 h PONV in Group Trp was also significantly lower than that in Group Dxm (P=0.042; odds ratio 0.359; 95% CI 0.157-0.819). There was no significant difference between Group Acu and Group Trp (P=0.857). The need for antiemetic rescue medication was similar in the three groups. All groups expressed similar patient satisfaction. CONCLUSIONS: Combined with dexamethasone, electrical acupoint stimulation or tropisetron is more effective in PONV prophylaxis than dexamethasone alone in gynaecological patients undergoing laparoscopic surgery. CLINICAL TRIAL REGISTRATION: NCT 02096835.

Tropisetron ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats.

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-α 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-α, 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-α, 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.

5-HT3 antagonist, tropisetron, ameliorates age-related renal injury induced by D-galactose in male mice: Up-regulation of sirtuin 1.

Objectives: The kidney ages faster than other organs due to changes in energy metabolism, mitochondrial dysfunction, and oxidative stress. This study looked into the anti-aging effect of tropisetron. Materials and Methods: D-galactose was administrated subcutaneously in a mouse model for eight weeks in order to induce renal aging. Three separate intraperitoneal doses of tropisetron (1, 3, and 5 mg/kg body weight) were given at the same time. We assessed markers of mitochondrial dysfunction, oxidative stress, and inflammation. Via Real-Time PCR, the expressions of genes linked to aging (SIRT1) and apoptosis (Bax and Bcl-2) were ascertained. In addition, an assessment of histopathological changes, blood urea nitrogen, and creatinine concentrations was done. Results: In kidney tissue, tropisetron reduces mitochondrial dysfunction and oxidative stress, which are caused by D-galactose-induced overproduction of inflammatory mediators. Additionally, tropisetron demonstrated antiapoptotic activity in renal tissue and augmented the decrease in SIRT1 gene expression associated with D-galactose administration. Besides, tropisetron significantly improved the histological alterations in the renal tissues of aged mice and effectively decreased the elevated levels of creatinine and also blood urea nitrogen. Conclusion: The results provided additional insight into the effect of tropisetron on renal aging and the underlying mechanisms, particularly through its ability to modulate SIRT1 signaling.

Effect of Prophylactic Tropisetron on Post-Operative Nausea and Vomiting in Patients Undergoing General Anesthesia: Systematic Review and Meta-Analysis with Trial Sequential Analysis.

This systematic review and meta-analysis of randomized controlled trials (RCTs) with trial sequential analysis (TSA) aimed to comprehensively evaluate and compare the efficacy of the prophylactic administration of tropisetron in the prevention of the incidence of post-operative nausea and vomiting (PONV) in patients undergoing surgery under general anesthesia. This study was registered with PROSPERO (CRD42024372692). RCTs comparing the efficacy of the perioperative administration of tropisetron with that of a placebo, other anti-emetic agents, or a combination of anti-emetic injections were retrieved from the databases of Ovid-MEDLINE, Ovid-EMBASE, the Cochrane Central Register of Controlled Trials, and Google Scholar. The frequency of rescue anti-emetic use (RA) and the incidence of PON, POV, and PONV (relative risk [RR]: 0.718; 95% confidence interval [CI] 0.652-0.790; I2 = 0.0, RR: 0.587; 95% CI 0.455-0.757; I2 = 63.32, RR: 0.655; 95% CI 0.532-0.806; I2 = 49.09, and RR: 0.622; 95% CI 0.552-0.700; I2 = 0.00, respectively) in the tropisetron group were lower than those in the control group; however, the incidence of complete response (CR) was higher in the tropisetron group (RR: 1.517;95% CI 1.222-1.885; I2 = 44.14). TSA showed the cumulative Z-curve exceeded both the conventional test and trial sequential monitoring boundaries for RA, PON, POV, and PONV between the tropisetron group and the control group. Thus, the prophylactic administration of tropisetron exhibited superior efficacy in the prevention of PON, POV, and PONV. Furthermore, a lower incidence of RA and a higher incidence of CR were observed with its use.

Evaluation of the effect of intraoperative tropisetron on postoperative rebound pain after brachial plexus block: a randomized controlled trial.

Introduction: Postoperative rebound pain after peripheral nerve block increases patient suffering and delays recovery after surgery. Objectives: We tested whether the 5HT-3 receptor antagonist and α7nAChR agonist tropisetron could prevent postoperative rebound pain. Methods: A total of 115 patients were randomized to receive 5-mg/5-mL tropisetron or the same volume of normal saline. Pain intensity was measured with the numerical rating scale of pain (NRS). Rebound pain was defined as a change from mild pain (NRS ≤ 3) measured in the postanesthesia care unit to severe pain (NRS ≥ 7) within 24 hours after peripheral nerve blockade. Logistic regression was used to identify relevant factors associated with postoperative rebound pain. Results: Tropisetron did not affect the NRS score or the incidence of rebound pain after peripheral nerve block. Logistic regression revealed that preoperative pain, bone surgery, and length of incision were risk factors for postoperative rebound pain, and patient-controlled analgesia was protective against postoperative rebound pain. Conclusion: Tropisetron does not affect the incidence of rebound pain after peripheral nerve block. Patients at high risk of postoperative rebound pain should be identified for appropriate management. Registration site: www.chictr.org.cn (ChiCTR2300069994).

Camel FGF21 Protein Enhances FGF21 Signaling and its Targeted Compounds Screening.

INTRODUCTION: The hormone Fibroblast Growth Factor 21 (FGF21), as a novel glucose and lipid metabolism regulator, has become a promising therapeutic target for metabolic disorders. Camel, the characteristic species adapted to arid and semi-arid desert climates, has shown exceptional ability for the regulation of lipid reserve and utilization. METHODS: This study found camel FGF21 to have a stronger regulatory effect for downstream signaling compared to human and mouse through sequence analysis and FGF21 signal downstream markers detection. FGF21 protein has been found to have one potential drug-binding pocket, which has been predicted using the CavityPlus online platform. Four small compounds, resorcinol monoacetate, tropisetron, nylidrin, and stiripentol, targeting FGF21 protein have been screened by molecular docking using the UCSF DOCK6 program. RESULTS: The inhibitory concentration 50% (IC50) values of the four small compounds have been determined by MTT assay and the values have been simulated by the software GraphPad Prism. The biological effect testing has indicated the four compounds to be involved in the regulation of the FGF21 signaling pathway and serve as agonists for FGF21 signaling transduction. While the blocking experiment of compound and protein cotreatment has indicated the four small compounds to not inhibit FGF21-induced pathway activation. Even, resorcinol monoacetate and stiripentol have shown to synergistically activate downstream signaling pathways with the FGF21 protein. CONCLUSION: This study has provided new ideas for developing therapeutic strategies based on FGF21 protein modification and exploring novel disease treatment strategies based on the compounds-protein combination.