15-Deoxy-δ12,14-prostaglandin J2 protects PC12 cells from LPS-induced Cell death through Nrf2 pathway in PPAR-γ dependent manner

Introduction: the inflammatory response requires a coordinated integration of various signaling pathway including cyclooxygenase (cox). cox catalyzes the formation of prostaglandins from arachidonic acid. among prostaglandins, 15-deoxy-d12, 14-prostaglandin j2 (15d-pgj2), an endogenous ligand of peroxisome proliferator-activated receptor-gamma (ppar-γ), has been demonstrated to have anti-inflammatory actions. in this study, we investigated whether 15d-pgj2 as a ppar-γ ligand could exert neuroprotective effects in rat pheochromocytoma (pc 12) cells in ppar-γ dependent manner. methods: in our experiment, using pc12 cells, the levels of nf-kb, nr£2, γ-glutamylcysteine synthetase (γ-gcs), hemeoxygenase (ho-1) and apoptosis factors were determined using western blot in different groups. also cell viability was determined by the conventional mtt (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) reduction assay and two staining involved hoechst staining and acridine ordange/ethidiume bromide staining respectively. results: our results show that ns-398, a selective cox-2 inhibitor and 15d-pgj2, a natural potent ligand of ppar-γ, were neuroprotective through modulation of at least three different, but related pathways and molecules, including nf-kb and nrf2 signaling pathway. our data showed that 15d-pgj2 and ns-398 induced nrf2 signaling pathway and its downstream factors such as ho-1 and γ-gcs, while 15d-pgj2 and ns-398 decreased nf-kb level. interestingly, the observed protective effects were mediated through ppar-γ-dependent mechanisms, as they reversed by gw9662, an irreversible antagonist of ppar-γ receptor. discussion: thus we conclude that 15d-pgj2 as well as ns-398 exert anti cell death effect in a ppar-y dependent mechanisms.