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Selective inhibition of cyclooxygenase (COX) isoenzymes and neuroinflammation
No full textMicroglia, 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 Huntingtons
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
"Fuzzy Reliability Analisys of Concrete Structures by using a Genetically Powered Simulation"
No full text"The softening and the bond slip influence on the nonlinear analysis of R.C. frame structures."
No full text"Il controllo della formulazione tangente per la soluzione di problemi strutturali non lineari."
No full textScuola di Specializzazione "F.lli Pesenti.", Politecnico di Milano
"Generazione di modelli strut-and-tie ed analisi non lineare della corrispondente risposta strutturale."
No full textScuola di Specializzazione "F.lli Pesenti.", Politecnico di Milan
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