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: Antonietta Bernardo, Maria Antonietta Ajmone-Cat, Laura Gasparini, Ennio Ongini, Luisa Minghetti
• Journal: Journal of neurochemistry (J Neurochem) Vol. 92 Issue 4 Pg. 895-903 (Feb 2005) ISSN: 0022-3042 [Print] England
• PMID: 15686492 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• PPAR gamma
• nitroflurbiprofen
• Flurbiprofen

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cells, Cultured
• Cerebral Cortex (drug effects, metabolism)
• Flurbiprofen (analogs & derivatives, pharmacology)
• Microglia (drug effects, metabolism)
• PPAR gamma (metabolism)
• Rats
• Rats, Wistar