The in vitro and in vivo anti-inflammatory effects of a phthalimide PPAR-γ agonist

Abstract

Previously, the authors found that 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione (PD1) (a phthalimide analogue) bound to and activated peroxisome proliferator-activated receptor- (PPAR-γ). Since PPAR-γ suppresses inflammatory responses, the present study was undertaken to investigate the anti-inflammatory effects of PD1. In lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, PD1 suppressed the inductions of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase 2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Concomitantly, PD1 enhanced the expressions of anti-inflammatory factors, such as arginase-1 and interleukin-10 (IL-10), and suppressed LPS-evoked nuclear factor kappa B (NF-κB) p65 subunit phosphorylation in macrophages. In addition, PPAR- activated by PD1 was intensively translocated to the nucleus. These observations suggest that the anti-inflammatory mechanism of PD1 involves inhibition of the NF-κB pathway. In a subsequent in vivo animal experiment conducted using a carrageenan-induced acute inflammatory rat paw edema model, intraperitoneal injection of PD1 significantly reduced paw swelling. Histological analysis of rat paw tissue sections revealed less infiltration of immune cells in PD1-pretreated animals. These findings suggest that PD1 be viewed as a lead compound for the development of novel anti-inflammatory therapeutics.