The group of professor Piomelli is looking for ways to increase the palmitoylethanolamide content in the body. This lead to the the discovery of N-acylethanolamine acid amidase inhibitors. These enzyme inhibitors inhibit the breakdown of our own palmitoylethanolamide. There are some drawbacks sadly with this approach. The molecules inhibiting our own enzyme systems are not natural and body-similar, and thus side effects occur. Furthermore, PEA synthesis is on demand, and giving enzyme inhibitors will be superposed on endogenous demand and synthesis. The question is whether that will lead to significant and clinical improvement. But his approach does point out the importance of palmitoylethanolamide for the body.
Palmitoylethanolamide is a potent or moderately potent agonists of the peroxisome proliferator-activated receptor- (PPAR-), a member of the nuclear receptor superfamily, which is responsible for most of their analgesic and anti-inflammatory properties, according to the writers. PEA is generated in many mammalian tissues, including in neurons and innate immune cells, where a selective phospholipase, N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) releases them by cleaving their membrane precursor, N-acylphosphatidylethanolamine.
The actions of PEA are terminated by enzyme-mediated hydrolysis, which is catalyzed by two known intracellular lipid amidases: Nacylethanolamine acid amidase (NAAA, previously referred to as N-acylethanolamine hydrolyzing acid amidase) and fatty acid amide hydrolase (FAAH.
Inhibiting these would increase endogenous PEA levels.