title: Cyclooxygenase-2 mediates anandamide metabolism in the mouse brain.
abstract: Cyclooxygenase-2 (COX-2) mediates inflammation and contributes to neurodegeneration. Best known for its pathological up-regulation, COX-2 is also constitutively expressed within the brain and mediates synaptic transmission through prostaglandin synthesis. Along with arachidonic acid, COX-2 oxygenates the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol in vitro. Inhibition of COX-2 enhances retrograde signaling in the hippocampus, suggesting COX-2 mediates endocannabinoid tone in healthy brain. The degree to which COX-2 may regulate endocannabinoid metabolism in vivo is currently unclear. Therefore, we explored the effect of COX-2 inhibition on [(3)H]AEA metabolism in mouse brain. Although AEA is hydrolyzed primarily by fatty acid amide hydrolase (FAAH), ex vivo autoradiography revealed that COX-2 inhibition by nimesulide redirected [(3)H]AEA substrate from COX-2 to FAAH in the cortex, hippocampus, thalamus, and periaqueductal gray. These data indicate that COX-2 possesses the capacity to metabolize AEA in vivo and can compete with FAAH for AEA in several brain regions. Temporal fluctuations in COX-2 expression were observed in the brain, with an increase in COX-2 protein and mRNA in the hippocampus at midnight compared with noon. COX-2 immunolocalization was robust in the hippocampus and several cortical regions. Although most regions exhibited no temporal changes in COX-2 immunolocalization, increased numbers of immunoreactive cells were detected at midnight in layers II and III of the somatosensory and visual cortices. These temporal variations in COX-2 distribution reduced the enzyme's contribution toward [(3)H]AEA metabolism in the somatosensory cortex at midnight. Taken together, our findings establish COX-2 as a mediator of regional AEA metabolism in mouse brain.
authors: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794-5230, USA. sherrye.glaser@stonybrook.edu
authors: Sherrye T
authors: ST
authors: Glaser
authors: Martin
authors: M
authors: Kaczocha
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001345:Autoradiography; D001682:Biological Availability; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D063388:Endocannabinoids; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013003:Somatosensory Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D014793:Visual Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013449:Sulfonamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide; C012655:nimesulide