title: Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility.
abstract: Focal cerebral ischemia (FCI) induces rapid neuronal death in the ischemic core, which gradually expands toward the penumbra, partly as the result of a neuroinflammatory response. It is known that propagation of neuroinflammation involves microglial cells, the resident macrophages of the brain, which are highly motile when activated by specific signals. However, the signals that increase microglial cell motility in response to FCI remain mostly elusive. Here, we tested the hypothesis that endocannabinoids mediate neuroinflammation propagation by increasing microglial cell motility. We found that, in mouse cerebral cortex, FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production. This potentiation of microglial cell migration by PEA involves reduction in cAMP levels. In line with this, we provide evidence that PEA acts through Gi/o-coupled receptors. Interestingly, these receptors engaged by PEA are pharmacologically distinct from CB1 and CB2 cannabinoid receptors, as well as from the WIN and abn-CBD (abnormal-cannabidiol) receptors, two recently identified cannabinoid receptors. Our results show that PEA and AEA increase after FCI and synergistically enhance microglial cell motility. Because such a response could participate in the propagation of the FCI-induced neuroinflammation within the CNS, and because PEA is likely to act through its own receptor, a better understanding of the receptor engaged by PEA may help guide the search for improved therapies against neuroinflammation.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Allyn
authors.initials: A
authors.lastname: Franklin
authors.forename: Sophie
authors.initials: S
authors.lastname: Parmentier-Batteur
authors.forename: Lisa
authors.initials: L
authors.lastname: Walter
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
mesh_terms: D000577:Amides; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002540:Cerebral Cortex / Q000378:metabolism; D063388:Endocannabinoids; D004983:Ethanolamines; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D010169:Palmitic Acids / Q000378:metabolism* / Q000494:pharmacology*; D010587:Phagocytosis; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism
chemical_list: D000577:Amides; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004983:Ethanolamines; D005231:Fatty Acids, Unsaturated; D005989:Glycerides; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D009569:Nitric Oxide; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D020962:Heterotrimeric GTP-Binding Proteins; C078814:anandamide