@article{830ccb5f5f834058b5aa60642cbce52f,
title = "Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain",
abstract = "Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.",
keywords = "Endocannabinoid, Lumiracoxib, cannabinoid, lipopolysaccharide, monoacylglycerol lipase, prostaglandin glyceryl esters, prostamide",
author = "Morgan, {Amanda J.} and Kingsley, {Philip J.} and Mitchener, {Michelle M.} and Megan Altemus and Patrick, {Toni A.} and Gaulden, {Andrew D.} and Marnett, {Lawrence J.} and Sachin Patel",
note = "Funding Information: *Mailing address: Departments of Psychiatry and Behavioral Sciences, Molecular Physiology & Biophysics, and Pharmacology, 2213 Garland Avenue, Medical Research Building IV, Rm 8425B, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail: sachin.patel@vanderbilt.edu. Phone: 615-936-7768. Fax: 615-322-1462. ORCID Amanda J. Morgan: 0000-0003-4974-1830 Lawrence J. Marnett: 0000-0002-7834-6285 Sachin Patel: 0000-0001-8052-520X Author Contributions A.J.M. generated and genotyped mice, performed in vivo experiments, and prepared tissue for analysis; P.J.K. performed LC-MS/MS analytical analysis; and M.M.M. performed Western blot experiments under supervision of S.P. and L.J.M. M.A., T.A.P., and A.D.G., contributed to mouse model generation, tissue preparation, and genotyping under supervision of S.P. A.J.M. and S.P. wrote the manuscript with input from all authors. Funding This work was supported by NIH Grants MH100096 (S.P) and S10OD017997. A.M. was supported by T32MH065215. Notes The authors declare the following competing financial interest(s): Vanderbilt University owns patent #14/415,977 entitled Compositions and Methods for Substrate-Selective Inhibition of Endocannabinoid Oxygenation. S.P. is a scientific consultant for Psy Therapeutics and has an active research contract with H. Lundbeck A/S. Publisher Copyright: {\textcopyright} Copyright 2018 American Chemical Society.",
year = "2018",
month = jul,
day = "18",
doi = "10.1021/acschemneuro.7b00499",
language = "English (US)",
volume = "9",
pages = "1552--1559",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "7",
}