Title

 

Authors

 O. Sasso¹, P. Busquet¹, D. Piomelli¹, R. Bertorelli¹ and A. Reggiani<sup>1

1</sup> Department of Drug Discovery and Development, Italian Institute of Tecnology, Via Morego, 30 16163 Genova, Italy

 

Abstract

 Ethanolamides of different long-chain fatty acids are a class of endogenous bioactive lipid molecules generally called N-acylethanolamines (NAEs). Within NAEs considerable attention have received N-arachidonoylethanolamide (anandamide), N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), because of their actions as endogenous cannabinoid receptor ligands (endocannabinoid). Identification of the biosynthetic routes and molecular characterization of the enzymes involved in the biosynthesis and degradation of NAEs are essential to better understanding their physiopathological importance. Until 2001, only Fatty Acid Amide Hydrolase (FAAH) was known as the major enzyme involved in the NAEs degradation. Subsequently, Ueda et al. found in rat tissues another enzyme involved in the NAEs degradation, the NAE-hydrolyzing acid amidase (NAAA) (1) and established that this enzyme had no homology to FAAH (2). Later studies revealed that NAAA is one of the lysosomal hydrolases (3) and more recently work by Solorzano et al (4) with NAAA inhibitor suggested that NAAA could be the target for the development of new drugs. The aim of the present study was to assess the effect of a new, potent and selective, non competitive NAAA inhibitor ARN0077 in a murine model of persistent pain. A single intraplantar or topical administration of ARN0077 showed a significant dose and time-dependent anti-edematogenic and anti-hyperalgesic effects in the model of carrageenan-induced paw edema in mice. The effect of ARN0077 was blocked by GW6471 suggesting that the effect was mediated by PPAR-alpha while neither AM 251 nor AM 630 were effective suggesting that neither CB1 nor CB2 receptors were involved in ARN0077 activity. Present studies suggest that the inhibition of NAAA can provide a significant analgesic and antiinflammatory efficacy via a non cannabinoid mechanism and confirm that NAAA inhibitors can become a novel drug class for inflammation driven disease states.

1. N. Ueda, K. Yamanaka and S. Yamamoto (2001) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem, 276: 35552–35557.
2. K. Tsuboi, Y.-X. Sun, Y. Okamoto, N. Araki, T. Tonai and N. Ueda (2005) Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem, 280: 11082–11092.
3.  K.Tsuboi, L.-Y. Zhao, Y. Okamoto, N. Araki, M. Ueno and H. Sakamoto et al. (2007) Predominant expression of lysosomal N-acylethanolamine-hydrolyzing acid amidase in macrophages revealed by immunochemical studies. Biochim Biophys Acta, 1771: 623–632.
4. Solorzano C, Zhu C, Battista N, Astarita G, Lodola A, Rivara S, Mor M, Russo R, Maccarrone M, Antonietti F, Duranti A, Tontini A, Cuzzocrea S, Tarzia G, Piomelli D (2009) Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci U S A., 106(49): 20966-71.