Nuclear receptor peroxisome proliferator‐activated receptor‐γ is activated in rat microglial cells by the anti‐inflammatory drug HCT1026, a derivative of flurbiprofen

The peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) 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‐γ agonistic properties. It has been proposed that PPAR‐γ 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‐α‐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‐γ and interfere with microglial activation. We found that a low concentration (1 µ m ) of HCT1026, but not flurbiprofen, activated PPAR‐γ in primary cultures of rat microglia, with kinetics similar to those of the synthetic agonist ciglitazone. The PPAR‐γ antagonist GW9662 (2‐chloro‐5‐nitrobenzanilide) prevented the activation of PPAR‐γ by HCT1026. Interestingly, unlike other NSAIDs that activate PPAR‐γ at concentrations higher than those required for cyclooxygenase inhibition, HCT1026 activated PPAR‐γ and inhibited prostaglandin E 2 synthesis at the same low concentration (1 µ m ). The results suggest that HCT1026 may exert additional anti‐inflammatory actions through PPAR‐γ activation, allowing a more effective control of microglial activation and brain inflammation.