title: Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases.
abstract: Type 1 vanilloid receptors (VR1) have been identified recently in the brain, in which they serve as yet primarily undetermined purposes. The endocannabinoid anandamide (AEA) and some of its oxidative metabolites are ligands for VR1, and AEA has been shown to afford protection against ouabain-induced in vivo excitotoxicity, in a manner that is only in part dependent on the type 1 cannabinoid (CB1) receptor. In the present study, we assessed whether VR1 is involved in neuroprotection by AEA and by arvanil, a hydrolysis-stable AEA analog that is a ligand for both VR1 and CB1. Furthermore, we assessed the putative involvement of lipoxygenase metabolites of AEA in conveying neuroprotection. Using HPLC and gas chromatography/mass spectroscopy, we demonstrated that rat brain and blood cells converted AEA into 12-hydroxy-N-arachidoylethanolamine (12-HAEA) and 15-hydroxy-N-arachidonoylethanolamine (15-HAEA) and that this conversion was blocked by addition of the lipoxygenase inhibitor nordihydroguaiaretic acid. Using magnetic resonance imaging we show the following: (1) pretreatment with the reduced 12-lipoxygenase metabolite of AEA, 12-HAEA, attenuated cytotoxic edema formation in a CB1 receptor-independent manner in the acute phase after intracranial injection of the Na+/K+-ATPase inhibitor ouabain; (2) the reduced 15-lipoxygenase metabolite, 15-HAEA, enhanced the neuroprotective effect of AEA in the acute phase; (3) modulation of VR1, as tested using arvanil, the VR1 agonist capsaicin, and the antagonist capsazepine, leads to neuroprotective effects in this model, and arvanil is a potent neuroprotectant, acting at both CB1 and VR1; and (4) the in vivo neuroprotective effects of AEA are mediated by CB1 but not by lipoxygenase metabolites or VR1.
authors.affiliation: Department of Experimental In Vivo Nuclear Magnetic Resonance, Image Sciences Institute, Utrecht, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: Veldhuis
authors.forename: M
authors.initials: M
authors.lastname: van der Stelt
authors.forename: M W
authors.initials: MW
authors.lastname: Wadman
authors.forename: G
authors.initials: G
authors.lastname: van Zadelhoff
authors.forename: M
authors.initials: M
authors.lastname: Maccarrone
authors.forename: F
authors.initials: F
authors.lastname: Fezza
authors.forename: G A
authors.initials: GA
authors.lastname: Veldink
authors.forename: J F G
authors.initials: JF
authors.lastname: Vliegenthart
authors.forename: P R
authors.initials: PR
authors.lastname: Bär
authors.forename: K
authors.initials: K
authors.lastname: Nicolay
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000502:physiology*; D001773:Blood Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001923:Brain Chemistry; D001931:Brain Mapping; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000378:metabolism*; D063388:Endocannabinoids; D004983:Ethanolamines / Q000032:analysis / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000502:physiology*; D008084:Lipoxygenase / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004983:Ethanolamines; D005231:Fatty Acids, Unsaturated; D018696:Neuroprotective Agents; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; C121153:arvanil; D010042:Ouabain; D009637:Masoprocol; D008084:Lipoxygenase; D002211:Capsaicin; C078814:anandamide