title: Anti-inflammatory and antioxidant properties of a new arylidene-thiazolidinedione in macrophages.
abstract: Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2⁻/⁻ mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2⁺/⁺ cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.
authors: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil.
authors: L A
authors: LA
authors: Faine
authors: M
authors: M
authors: Rudnicki
authors: F A
authors: FA
authors: César
authors: B L
authors: BL
authors: Heras
authors: L
authors: L
authors: Boscá
authors: E S
authors: ES
authors: Souza
authors: M Z
authors: MZ
authors: Hernandes
authors: S L
authors: SL
authors: Galdino
authors: M C A
authors: MC
authors: Lima
authors: I R
authors: IR
authors: Pitta
authors: D S P
authors: DS
authors: Abdalla
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D045162:Thiazolidinediones; D000077154:Rosiglitazone