PPARγ, NF-κB and the UPR pathway as new molecular targets in the anti-inflammatory actions of NSAIDs: Novel applications in cancers and central nervous system diseases?

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, or celecoxib have a well-established and unquestionable role in the human therapeutic arsenal, but still new perspectives are being discovered. This review presents new anti-inflammatory mechanisms of NSAIDs action, other than the classical one, i.e., the inhibition of cyclooxygenase (COX) isoforms leading to the prostanoids synthesis blockage. Literature data show that this group of drugs can activate anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ), inhibit pro-inflammatory nuclear factor-κB (NF-κB) activation or modulate the components of the unfolded protein response (UPR) pathway. These alternative pathways induced by NSAIDs may not only enhance their basic anti-inflammatory mechanism of action but also promote other effects of the drugs such as anti-cancer. It was also proved that neuroinflammation, with the involvement of NF-κB, PPARγ and the components of the UPR pathway has an essential impact on the development of central nervous system (CNS) diseases. Thus, it seems possible that these new molecular targets may expand the use of NSAIDs, e.g., in the treatment of cancers and/or CNS disorders.