title: Simultaneous inhibition of COX-2 and activation of PPAR-γ resulted in the same level and pattern of neuroprotection as they were targeted separately.
abstract: The inflammatory response is an immune response of the body when exposed to internal and external stimuli. Cyclooxygenases (COX) are major inflammatory mediators implicated in inflammation. COX-2 is reported to be involved in neuroinflammation. Moreover, 15-Deoxy-D                 (12,14)-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 co-therapy of a selective COX-2 inhibitor NS-398 and 15d-PGJ2 as a PPAR-γ ligand could exert additional neuroprotective effects in rat pheochromocytoma (PC12) cells. Our findings showed that 15d-PGJ2 and NS-398 suppress the apoptotic pathway in PC12 cells exposed to H(2)O(2) by attenuation of the Bax/Bcl-2 ratio. This effect was mediated through PPAR-γ, as it was reversed by GW9662 (a PPAR-γ inhibitor). Also, 15d-PGJ2 and NS-398 induced the Nrf2 signaling pathway and decreased NF-κB level in a PPAR-γ-dependent manner. We found that coadministration of a selective COX-2 inhibitor and a PPAR-γ ligand in PC12 cells has equal neuroprotective effect compared to their effects when used separately. Considering the higher affinity of 15d-PGJ2 for PPAR-γ than NS-398, it seems that the observed neuroprotection of this combination therapy was from 15d-PGJ2.
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Shahnaz Babaei
authors.initials: SB
authors.lastname: Abraki
authors.forename: Leila
authors.initials: L
authors.lastname: Khalaj
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Shaerzadeh
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000032:analysis; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology; D016716:PC12 Cells; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000032:analysis
chemical_list: C477819:15-deoxyprostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D052246:Cyclooxygenase 2 Inhibitors; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D006861:Hydrogen Peroxide; D015230:Prostaglandin D2