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.

Tropisetron inhibits high glucose-induced calcineurin/NFAT hypertrophic pathway in H9c2 myocardial cells.

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 Ca(2+) 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 Ca(2+) 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.

The cardioprotective effects of an antiemetic drug, tropisetron, on cardiomyopathy related to doxorubicin.

Cardiotoxicity is a life-threatening side effect of doxorubicin (DOX). Although the responsible mechanisms are largely unknown, it is demonstrated that DOX induces an elevation in the level of creatine kinase isoenzyme, lactic dehydrogenase, creatine phosphokinase, and troponin T in serum and reduces body/heart weight. In addition, cardiotoxicity is further confirmed by changes in ECG parameters and papillary muscle contractile force. Tropisetron is an effective antiemetic drug for chemotherapy-induced emesis. There is ample evidence that tropisetron exerts immune modulatory and anti-inflammatory properties. The present study was designed to investigate the protective effects of tropisetron pretreatment against DOX-induced cardiotoxicity in rats. In this study, DOX toxicity was induced by a single intraperitoneal injection (15 mg/kg), and in treated group, tropisetron (3 mg/kg; i.p) was administered 1 h prior to DOX injection. Our results indicated that tropisetron potently decreased body/heart weight loss and mortality rate and also improved ECG changes as well as heart contractility. In addition, tropisetron robustly counteracted the increase in the levels of serum biomarkers and alleviated the histopathological changes in rats' hearts as compared with the DOX group. Taken together, these results demonstrate that tropisetron has potent cardioprotective effects against DOX-induced cardiotoxicity.