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PhD Thesis: Chenggang Zhu

Dissertation Abstract:
An Endogenous Role of Palmitoylethanolamide in Inflammation

By Chenggang Zhu
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2009
Professor Daniele Piomelli, Chair

The fatty acid ethanolamides (FAEs) are a family of signaling lipids involved in various physiological processes including the control of feeding, pain and inflammation. The best characterized member of this family of signaling molecules is the endocannabinoid anandamide, which exerts its multiple biological effects through activation of cannabinoid receptors, CB1 and CB2.

Despite the common basic structure of the FAEs, the effects of two other members of this class, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are not due to cannabinoid receptor activation, but rather to activation of the nuclear receptor, peroxisome proliferator-activated receptor type alpha (PPAR-α). PEA was isolated from plant and animal tissues over 50 years ago. Soon after its discovery, it was shown to reduce allergic reactions and inflammation in animals, and was briefly used to treat influenza symptoms in humans. However, the endogenous roles of PEA remain elusive. In the present dissertation, I used an experimental approach combining molecular, biochemical, and pharmacological techniques to elucidate the endogenous regulatory mechanisms of PEA. I found that tissues PEA levels are markedly reduced during inflammation and that this effect is due to the down-regulation of the PEA-synthesizing enzyme, N-acylphosphatidylethanolamine specific phospholipase D (NAPE-PLD) through a molecular mechanism that involves chromatin remodeling. Additionally, in collaboration with medicinal and computational chemists, I discovered the first potent and selective inhibitors of the PEA-hydrolyzing enzyme, N-acylethanolamine-hydrolyzing acid amidase (NAAA), and showed that these agents exert profound anti-inflammatory effects in inflammation models.

Together, the characterization of the PEA regulatory mechanism and the pharmacological tools aiming at elevating endogenous PEA levels by blockade of its hydrolysis have helped to broaden our current understanding of the mechanisms that underlie PEA signaling during inflammatory responses, and will serve as useful tools by which to gain further knowledge on the biological roles of this lipid amide.