Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

T2DM is a multi-pathological disease that entails several organs, including skeletal muscle and brain. Serotonin (5-HT), synthesized within Ý-cells, stored and co-secreted with insulin, raising the curiosity regarding its possible role in diabetes. Hence, the aim of this study was to assess the possible modulatory effects of Tropisetron (Trop), a 5-HT3 receptor antagonist, on T2DM in rats. Animals were allocated into normal and diabetic rats. Diabetic rats were treated with Metformin (500 mg/kg, p.o; Met.), Tropisetron (1 and 2 mg/kg, i.p; Trop1 & 2), or combination of Met. with Trop1. In serum, all treatment regimens, especially Trop1, improved glucose/lipid homeostasis (glucose, fructosamine, insulin, TGs, TC, FFAs). Trop1 and its combination decreased serum RAGE level and increased 5-HT; however, Trop1&2 and Met increased hippocampal 5- HT and insulin. The Trop-mediated improvement in muscular (Phosphorylated insulin receptor substrate 1; pIRS1, protein kinase B; AKT and Glucose transporter 4; GLUT4) and hippocampal (AKT, GLUT4) insulin signaling pathway may be partially responsible for the overall corrected picture. Additionally, muscular/hippocampal contents of Ý-catenin and NF-mB were decreased in Trop1&2 treated rats, pointing for the possible role of Wnt pathway in the Trop. action. In conclusion the study provided evidence for the role of Tropisetron on T2DM, via modulating theinsulin signaling cascade (insulin, pIRS1, AKT, GLUT4), improving lipid/glucose profile, decreasing inflammatory markers (RAGE, NF-mB), as well as increasing serotonin, and reducing Ý-catenin

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