Avaliação do potencial antiglicante e atividade antidiabética de novas aminoguanidinas e derivados planejados no modelo de diabetes induzida pela estreptozotocina

Abstract

Diabetes mellitus (DM) is considered a health problem all over the world. Characterized by a group of metabolic disorders resulting from defects in insulin secretion, insulin action or both. One of the major problems arising from the disease is the complications from chronic hyperglycemia and these complications have a direct relationship with the accumulation of advanced glycation products (AGEs). Different substances have been studied as strategies for the prevention of complications of diabetes, especially substances with potential anti-graft, such as aminoguanidine. In order to discover new active compounds capable of inhibiting the formation of advanced glycation products, aminoguanidine derivatives were designed, which evaluated their antiglanding action and the antidiabetic activity was evaluated. For the evaluation of the antiglicante activity, the AGEs were produced using bovine serum albumin (BSA) and glucose as the glycator. Of the 22 aminoguanidine derivatives studied, 4 of them showed inhibition results below 50%, 8 with inhibition percentages between 50 and 69%, 10 compounds showed percent inhibition above 70%. The compounds LQM 103, LQM 130, LQM 140 and LQM 141 showed the best results, with respectively 95, 94, 98 and 99% inhibition of AGEs during the 56 days of incubation, showing to have a strong anti-AGE potential. Cellular cytotoxicity assay was performed in vitro by cell viability (MTT-tetrazolium). MTT results indicated that the aminoguanidine derivatives tested did not show cytotoxicity against 3T3 fibroblasts at concentrations of 10 and 100 μM. Only the compound LQM 98 showed 10 μM cytotoxicity against J774A.1 macrophages cells, although this compound was among those that showed 70% inhibition of the formation of advanced glycation end products. The most promising compounds were selected for the in vivo study of acute and antidiabetic toxicity. No evidence of acute toxicity was observed at ponderal, hematological, serological and histological biochemical levels. In the antidiabetic assay, the aminoguanidine derivatives promoted a glycemic reduction in treated animals up to 60%. In this way, it can be inferred that the aminoguanidine derivatives LQM 140 and LQM 141 were the most promising ones directed to the antiglicante and antidiabetic activity. However, further studies need to be carried out to better understand the relationships between DM, the antiglican activity of aminoguanidine derivatives, in order to elucidate the mechanisms of action and to establish the therapeutic potential of these compounds for diabetic patients and to prevent the chronic complications that accompany hyperglycemia.