title: Nuclear receptor peroxisome proliferator-activated receptor-gamma is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen.
abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is constitutively expressed in primary cultures of rat microglia, the main population of brain resident macrophages, and its ligand-dependent activation leads to the repression of several microglial functions. A few non-steroidal anti-inflammatory drugs (NSAIDs), e.g. indomethacin and ibuprofen, show PPAR-gamma agonistic properties. It has been proposed that PPAR-gamma activation contributes to the potential benefits of the long-term use of certain NSAIDs in delaying the progression of Alzheimer's disease (AD). Previous data have shown that the NSAID HCT1026 [2-fluoro-alpha-methyl(1,1'-biphenyl)4-acetic acid-4-(nitrooxy)butyl ester], a derivative of flurbiprofen which releases nitric oxide (NO), reduces the number of reactive microglial cells in a variety of models. This evidence together with the chemical analogy with ibuprofen led us to investigate whether flurbiprofen and HCT1026 interact with PPAR-gamma and interfere with microglial activation. We found that a low concentration (1 microm) of HCT1026, but not flurbiprofen, activated PPAR-gamma in primary cultures of rat microglia, with kinetics similar to those of the synthetic agonist ciglitazone. The PPAR-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) prevented the activation of PPAR-gamma by HCT1026. Interestingly, unlike other NSAIDs that activate PPAR-gamma at concentrations higher than those required for cyclooxygenase inhibition, HCT1026 activated PPAR-gamma and inhibited prostaglandin E2 synthesis at the same low concentration (1 microm). The results suggest that HCT1026 may exert additional anti-inflammatory actions through PPAR-gamma activation, allowing a more effective control of microglial activation and brain inflammation.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bernardo
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Ajmone-Cat
authors.forename: Laura
authors.initials: L
authors.lastname: Gasparini
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Luisa
authors.initials: L
authors.lastname: Minghetti
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047495:PPAR gamma; C095631:nitroflurbiprofen; D005480:Flurbiprofen