Harnessing the anti-inflammatory potential of palmitoylethanolamide

Palmitoylethanolamide (PEA) is a peroxisome proliferator-activated receptor alpha (PPAR-α) ligand that exerts anti-inflammatory, analgesic and neuroprotective actions. PEA is synthetized from phospholipids through the sequential actions of N-acyltransferase and N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD), and its actions are terminated by its hydrolysis by two enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolysing acid amidase (NAAA). Here, we review the impact of PEA administration in inflammatory and neurodegenerative settings and the differential role of FAAH and NAAA in controlling PEA levels. Recent studies with NAAA inhibitors put forth this enzyme as capable of increasing PEA levels in vivo in inflammatory processes, and identified it as an interesting target for drug discovery research. Thus, PEA hydrolysis inhibitors could constitute potential therapeutic alternatives in chronic inflammatory and neurodegenerative diseases.