Selective inhibition of cyclooxygenase (COX) isoenzymes and neuroinflammation

Microglia, the immune cells of the brain, are one of the key mediators of neuroinflammation. Microglial activation leads these cells to produce various proinflammatory and neurotoxic substances. Several in vitro and in vivo studies have demonstrated that a decrease in the levels of pro-inflammatory mediators in microglia can attenuate the severity of neuro-degenerative diseases, including AD, PD, ALS, MS and Huntington’s disease. Thus, regulation of excessive microglial activation should be of therapeutic value especially in neuro-degenerative disorders. Cyclooxygenase(COX) is a key enzyme in the conversion of arachidonic acid into prostaglandins and other lipid mediators. It is widely accepted that this enzyme play a pivotal role in the neuro-inflammatory process exacerbation. Two COX isoforms are known: COX-1, constitutively expressed in most tissues, classically considered as the isoform primarily responsible for maintaining the homeostasis by mediating physiological responses, and COX-2, which represents the inducible form, mainly activated in response to inflammatory stimuli. In this respect, recent studies have also indicated a previously unrecognized pro-inflammatory role of COX-1 in the pathophysiology of acute and chronic neurological disorders. Consequently, it was reconsidered the potential beneficial effect of COX-1 inhibition in the treatment of neuroinflammation [1]. These findings prompted us to investigate the behaviour of two selective COX-1 inhibitors such as P6 (COX-1 IC50= 0.5 mM and COX-2 IC50 >100 mM) and P10 (COX-1 IC50= 0.09 mM and COX-2 IC50 = 2.49 mM) [2] in an in vitro experimental model of inflammation, represented by mouse N13 microglial cells activated by lipopolysaccharide (LPS) [3]. LPS is a component of the outer cell wall of gramnegative bacteria and is well known as an inducer of inflammatory responses. New selective COX-1 inhibitors are here proposed also as useful tools in pharmacological studies to investigate the role of COX-1 isoenzyme in neuroinflammation or more in general in all the investigations in which only COX-1 needs to be selectively inhibited. The results of this study as well as their rationale will be presented and discussed. References: 1. Perrone, M.G.; Scilimati, A.; Simone, L., Vitale, P. Curr. Med. Chem.2010,17, 3769-805. 2. Di Nunno. L., Vitale, P., Scilimati, A., Tacconelli, S.; Patignani, P. J. Med. Chem. 2004, 47, 4881-90. 3. Calvello, R.; Panaro, M.A.; Carbone, M.L.; Cianciulli, A.; Perrone, M.G.; Vitale, P.; Malerba, P.; Scilimati, A. Biochem. Pharmacol.,2011, submitted for publication.