Beyond the 5-HT3 receptors: A role for α7nACh receptors in neuroprotective aspects of tropisetron.

Accumulation of reactive oxygen species, such as hydrogen peroxide (H2O2), generated by inflammatory cells or other pathological conditions, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders such as Alzheimer's disease. Recent investigations have described effective properties of tropisetron, such as antiphlogistic action or protection against ß-amyloid induced-neuroinflammation in rats. Our data revealed that H2O2-induced cell death in rat pheochromocytoma cell line (PC12) can be inhibited by tropisetron, as defined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay, caspase 3 and caspase 12 levels. We further showed that tropisetron exerts its protective effects by upregulation of heme oxygenase-1, glutathione, catalase activity, and nuclear factor-erythroid 2 p45-related factor 2 level. Moreover, tropisetron was recently found to be a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). The activation of α7nAChR could inhibit inflammatory and apoptotic signaling pathways in the oxidative stress conditions. In this study, selective α7nAChR antagonists (methyllycaconitine) reversed the effects of tropisetron on caspase 3 level. Our findings indicated that tropisetron can protect PC12 cells against H2O2-induced neurotoxicity through α7nAChR in vitro.

Anti-inflammatory effects of 5-HT receptor antagonist, tropisetron on experimental colitis in rats.

BACKGROUND: There is a pressing need for research that will lead to the development of new therapeutic approaches for treating inflammatory bowel disease (IBD). The aim of this study was to investigate the effects of tropisetron, a 5-Hydroxytryptamine (5-HT)-3 receptor antagonist with anti-inflammatory properties in a model of experimental colitis in rat. MATERIALS AND METHODS: Acetic acid model of colitis in rats was used. Colitis was induced by intracolonal instillation of 4% (v/v) acetic acid. One hour after induction of colitis, intraperitoneal (IP) or intrarectal (IR) tropisetron (2 mg kg(-1), either route) or dexamethasone (1 mg kg(-1), either route) was administered. The severity of colitis was assessed 24 h later using macroscopic and microscopic changes of damaged colon, measurement of inflammatory cytokines interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha levels and oxidative stress markers myeloperoxidase (MPO) and malondialdehyde (MDA) in colonic tissues. RESULTS: Tropisetron decreased colonic macroscopic and microscopic damage scores. This was associated with significant reduction in both neutrophil infiltration indicated by decreased colonic MPO activity and lipid peroxidation measured by MDA content, as well as a decreased colonic inflammatory cytokines. IR tropisetron decreased colonic damage that was associated with decreased neutrophil infiltration, lipid peroxidation and colonic inflammatory cytokines. Beneficial effects of tropisetron were lower than those of dexamethasone. No significant differences were observed between IP and IR administration with the exception of MDA level more diminished by IP tropisetron and dexamethasone. CONCLUSIONS: Tropisetron exert beneficial effects in experimental rat colitis and therefore might be useful in the treatment of IBD.