Diabetes and Obesity Drug Discovery & Therapy (Track)

Anti-inflammatory and antioxidant effects of a new arylidene-thiazolidinedione on macrophages

D.S.P. Abdalla
Department of Clinical and Toxicology Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, 05508-900, Sao Paulo, Brazil

Abstract:

Thiazolidinediones (TZDs) have been extensively studied for their hypoglycemic effects. However, several side effects are associated with TZDs treatment making necessary the search for improved compounds. The new arylidene-thiazolidinedione (SF-23), a modified TZD, was evaluated in this study for its anti-inflammatory and antioxidant effects and compared to roziglitazone, a well established TZD. SF-23 and roziglitazone diminished nitrite production, as well as, iNOS and COX-2 protein expression in lipopolysaccharide (LPS)-stimulated macrophages. The anti-inflammatoy effects can be due to their PPAR gamma ligand activity. However, SF-23 was demonstrated to be a weak PPAR gamma ligand, compared to rosiglitazone, since PPAR gamma expression and CD36 expression, a major target gene for PPAR gamma activity were lower in SF-23 treated macrophages, compared to rosiglitazone. The difference between SF-23 and roziglitazone was also observed at the antioxidant level. SF-23, but not rosiglitazone, induced prevention of LPS-induced mitochondrial membrane hyperpolarization. In addition, in the macrophages from knockout mice for the Nrf2 gene (Nrf2 -/-), the treatment with SF-23 induced protection against LPS-induced cellular death. Rosiglitazone was only able to protect normal Nrf2+/+ cells against oxidative injury. Thus, opposed to rosiglitazone, the SF-23 antioxidant activity was Nrf2-independent. Determinations of NADPH oxidase subunits in treated macrophages revealed that SF-23 exerts its antioxidant effects by decreasing Nox1 and Nox2 expression, consequently diminishing reactive oxygen species (ROS) generation. Concluding, the antioxidant properties of this new arylidene-thiazolidinedione were clearly demonstrated when compared to roziglitazone. Further studies on this compound are warranted, as SF-23 may constitute a potential drug with beneficial effects for the treatment of inflammatory and oxidative stress conditions observed in diabetes.