TY - JOUR
T1 - Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain
AU - Petrosino, Stefania
AU - Ahmad, Akbar
AU - Marcolongo, Gabriele
AU - Esposito, Emanuela
AU - Allarà, Marco
AU - Verde, Roberta
AU - Cuzzocrea, Salvatore
AU - Di Marzo, Vincenzo
N1 - Publisher Copyright:
© 2014 Published by Elsevier Ltd.
PY - 2015/1
Y1 - 2015/1
N2 - Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin.
AB - Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin.
KW - Diacerein
KW - Inflammation
KW - NAAA
KW - Palmitoylethanolamide
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U2 - 10.1016/j.phrs.2014.10.008
DO - 10.1016/j.phrs.2014.10.008
M3 - Article
C2 - 25447594
AN - SCOPUS:84910619396
SN - 1043-6618
VL - 91
SP - 9
EP - 14
JO - Pharmacological Research
JF - Pharmacological Research
ER -