| Literature DB >> 32393901 |
Elliot D Mock1, Mohammed Mustafa2, Ozge Gunduz-Cinar3, Resat Cinar4, Gavin N Petrie5, Vasudev Kantae1,6, Xinyu Di6, Daisuke Ogasawara7, Zoltan V Varga8, Janos Paloczi8, Cristina Miliano9, Giulia Donvito2, Annelot C M van Esbroeck1, Anouk M F van der Gracht1, Ioli Kotsogianni1, Joshua K Park4, Andrea Martella1, Tom van der Wel1,10, Marjolein Soethoudt1, Ming Jiang1,10, Tiemen J Wendel1, Antonius P A Janssen1,10, Alexander T Bakker1, Colleen M Donovan3, Laura I Castillo3, Bogdan I Florea11, Jesse Wat12, Helma van den Hurk12, Matthias Wittwer13, Uwe Grether13, Andrew Holmes3, Constant A A van Boeckel1,12, Thomas Hankemeier6, Benjamin F Cravatt7, Matthew W Buczynski9, Matthew N Hill5, Pal Pacher8, Aron H Lichtman2,14, Mario van der Stelt15,16.
Abstract
N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.Entities:
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Year: 2020 PMID： 32393901 PMCID： PMC7468568 DOI： 10.1038/s41589-020-0528-7
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040