Abstract
N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator-activated receptor-α. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors.
Highlights
The amides of long-chain fatty acids with ethanolamine, or fatty acid ethanolamides (FAEs), are a family of bioactive lipids that participate in the control of multiple physiological functions, including pain and inflammation.[1,2,3,4]
The actions of these lipid messengers are terminated by enzyme-mediated hydrolysis, which is catalyzed by two known intracellular lipid amidases: N-acylethanolamine acid amidase (NAAA, previously referred to as N-acylethanolamine hydrolyzing acid amidase)[14,15,16] and fatty acid amide hydrolase (FAAH).[17,18]
Topical application of ARN077 dose-dependently reduced UVB-induced heat hyperalgesia in rats whose glabrous skin of the hind paw was exposed to UVB radiation. These studies showed that ARN077 normalized the levels of PEA and OEA, but not anandamide, in inflamed tissues of mice, and that its antinociceptive effects were prevented by the selective peroxisome proliferator-activated receptor-α (PPAR-α) antagonist GW6471 and were absent in PPAR-α-deficient mice. These findings suggest that ARN077 modulated nociceptive responses in mice and rats by blocking NAAA-mediated FAE degradation and restoring FAE signaling at PPAR-α.[46]
Summary
The amides of long-chain fatty acids with ethanolamine, or fatty acid ethanolamides (FAEs), are a family of bioactive lipids that participate in the control of multiple physiological functions, including pain and inflammation.[1,2,3,4] Polyunsaturated FAEs such as arachidonoylethanolamide (anandamide, Fig. 1) are endogenous agonists for G proteincoupled cannabinoid receptors and participate in the control of stress-coping responses and pain initiation.[1,5] On the other hand, monounsaturated and saturated FAEs, such as oleoylethanolamide (OEA, Fig. 1) and palmitoylethanolamide (PEA, Fig. 1), are potent or moderately potent agonists of the peroxisome proliferator-activated receptor-α (PPAR-α), a member of the nuclear receptor superfamily, which is responsible for most of their analgesic and anti-inflammatory properties. [4,6,7]. FAEs are not stored in cells, but rather are produced on demand from cell membrane precursors.[8,9,10] OEA and PEA are generated in many mammalian tissues, including neurons[11] and innate immune cells,[12] where a selective phospholipase, Nacylphosphatidylethanolamine phospholipase D (NAPE-PLD) releases them by cleaving their membrane precursor, N-acylphosphatidylethanolamine.[13] The actions of these lipid messengers are terminated by enzyme-mediated hydrolysis, which is catalyzed by two known intracellular lipid amidases: N-acylethanolamine acid amidase (NAAA, previously referred to as N-acylethanolamine hydrolyzing acid amidase)[14,15,16] and fatty acid amide hydrolase (FAAH).[17,18] These enzymes share the ability to cleave lipid amide bonds, but differ in primary structure, substrate selectivity, and cellular localization. This review will describe the most representative inhibitors and will briefly highlight their pharmacological profile
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