Chapter 7. Inhibition of NAPE-PLD Activity by Natural Compounds and Synthetic Drugs, and Its Biological Relevance

In mammals, the endocannabinoid anandamide is biosynthesized from N-arachidonoyl-phosphatidylethanolamine by the enzyme N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD). Importantly, NAPE-PLD also produces other bioactive N-acylethanolamines, including anti-inflammatory palmitoylethanolamide and appetite-suppressive oleoylethanolamide, from their corresponding N-acyl-phosphatidylethanolamines (NAPEs). The analyses of NAPE-PLD-deficient mice revealed remarkable accumulation of NAPEs in brain and several peripheral tissues, suggesting the central role in NAPE degradation. On the other hand, the endogenous levels of N-acylethanolamines, including anandamide, were significantly decreased or almost unchanged, probably depending on co-existing NAPE-PLD-independent alternative pathways. The phenotypes of NAPE-PLD-deficient mice suggested the physiological and pathophysiological roles of NAPE-PLD in appetite, energy metabolism, and inflammation. So far, the reported inhibitors are not highly specific for NAPE-PLD, and potent specific inhibitors are under development.