Inhibition of human islet amyloid polypeptide or amylin aggregation by two manganese-salen derivatives

Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic fibrillar deposits has been postulated to be one of the main contributors to impaired insulin secretion and pancreatic beta-cell death in approximately 90% of type 2 diabetic patients. So, compounds that prevent cytotoxic protein/polypeptide self-assembly and amyloidogenesis are considered as novel therapeutic agents against this disease. In this study, using thioflavin-T (ThT) and Anilinonaphthalene-8-sulfonic acid (ANS) fluorescence assays, transmission electron microscopy (TEM) and docking studies, we investigated whether EUK-8 and EUK-134, two salen derivatives with proven antioxidants activities, could interfere with the conversion of synthetic human amylin to its insoluble amyloid form. Spectroscopy and electron microscopy data indicated that incubation of human amylin with either EUK-8 or EUK-134 significantly inhibited amyloid formation at two molar ratios of 1:1 and 5:1 (drugs to protein). In addition, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MU) assay showed that treatment of SK-N-MC cells with the preformed fibrils in the presence of compounds at drug-to-protein molar ratios of 1:1 and 5:1, dramatically increased the viability of cells compared to the only fibrils formed-treated SK-N-MC cells. Docking results also demonstrated that the aromatic rings of EUK-8 and EUK-134 interact with the hydrophobic region (23-25) of IAPP via Van der Waals interactions. Based on these results and the proven antioxidant properties of these compounds, it could be concluded that these compounds might provide a novel approach to prevent islet amyloid deposition in beta-cells and provide useful information for developing other novel compounds for the treatment of type 2 diabetes. (C) 2013 Elsevier B.V. All rights reserved.