Anti-diabetic properties of a non-conventional radical scavenger, as compared to pioglitazone and exendin-4, in streptozotocin-nicotinamide diabetic mice

作者：Novelli Michela; Canistro Donatella; Martano Manuela; Funel Niccola; Sapone Andrea; Melega Simone; Masini Matilde; De Tata Vincenzo; Pippa Anna; Vecoli Cecilia; Campani Daniela; De Siena Rocco; Soleti Antonio; Paolini Moreno; Masiello Pellegrino^*

来源：European Journal of Pharmacology, 2014, 729: 37-44.

DOI：10.1016/j.ejphar.2014.01.071

• Type 2 diabetes mellitus
• Oxidative stress
• Radical scavengers
• PDX-1
• Pioglitazone
• Exendin-4

We previously showed that the innovative radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC) improves metabolic dysfunctions in a diabetic mouse model. Here, we compared the in vivo effects of IAC with those of the anti-diabetic drugs pioglitazone (PIO) and exendin-4 (EX-4). Diabetes was induced in C57BI/6J mice by streptozotocin and nicotinamide administration. Paralleled by healthy controls, diabetic animals (D) were randomly assigned to four groups and treated daily for 7 consecutive weeks: D I saline, ip; D+IAC 30 mg/kg b.w., ip; D+PIO 10 mg/kg b.w. per os; and D+EX-4, 50 mu g/kg b.w., ip. Our results show that LAC reduced basal hyperglycemia and improved glucose tolerance better than PIO or EX-4. Interestingly, in the heart of diabetic mice, IAC treatment normalized the increased levels of GSSG/GSH ratio and thiobarbituric acid reactive substances, indexes of oxidative stress and damage, while PIO and EX-4 were less effective. As supported by immunohistochemical data, IAC markedly prevented diabetic islet beta-cell reduced density, differently from PIO and EX-4 that had only a moderate effect. Interestingly, in diabetic animals, IAC treatment enhanced the activity of pancreatic-duodenal homeobox 1 (PDX-1), an oxidative stress-sensitive transcription factor essential for maintenance of beta-cell function, as evaluated by quantification of its nuclear immunostaining, whereas PIO or EX-4 treatments did not. Altogether, these observations support the improvement of the general redox balance and beta-cell function induced by IAC treatment in streptozotocin-nicotinamide diabetic mice. Furthermore, in this model, the correction of diabetic alterations was better obtained by treatment with the radical scavenger IAC than with pioglitazone or exendin-4.

• 出版日期2014-4-15