Dynamic regulation of microglial functions by the non-steroidal anti-inflammatory drug NCX 2216: implications for chronic treatments of neurodegenerative diseases

Abstract

The nitric oxide-releasing derivative of flurbiprofen, NCX 2216, has a safer gastrointestinal profile than the parent drug flurbiprofen and a strong anti-amyloidogenic activity. Here, we show that in primary microglial cultures, in addition to the expected inhibition of prostaglandin synthesis, NCX 2216 specifically activated the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-dependent transcription factor controlling several important microglial functions. Prolonged treatment (16 h) of microglial cultures with NCX 2216 induced PPAR-gamma nitration and prevented further activation of the receptor by specific agonists. At functional levels, NCX 2216 treatment of LPS-activated microglial cultures resulted in the transient reduction of TNF-alpha and NO production and in the protracted inhibition of IL-1beta and PGE2 synthesis. The dynamic regulation of the functional state of activated microglia by NCX 2216 helps explaining recent findings in Alzheimer's disease animal models and may offer new therapeutic opportunities for treating neurodegenerative diseases.