title: Exogenous anandamide protects rat brain against acute neuronal injury in vivo.
abstract: The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 +/- 15% in a manner insensitive to the cannabinoid CB(1) receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 +/- 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8, or 24 hr after ouabain injection; (2) application of SR141716A alone did not increase the lesion volume at days 0 and 7; and (3) the AEA-uptake inhibitor, VDM11, did not affect the lesion volume. These data indicate that there was no endogenous endocannabinoid tone controlling the acute neuronal damage induced by ouabain. Although our data seem to question a possible role of the endogenous cannabinoid system in establishing a brain defense system in our model, AEA may be used as a structural template to develop neuroprotective agents.
authors.affiliation: Department of Bio-organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van der Stelt
authors.forename: W B
authors.initials: WB
authors.lastname: Veldhuis
authors.forename: G W
authors.initials: GW
authors.lastname: van Haaften
authors.forename: F
authors.initials: F
authors.lastname: Fezza
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: P R
authors.initials: PR
authors.lastname: Bar
authors.forename: G A
authors.initials: GA
authors.lastname: Veldink
authors.forename: J F
authors.initials: JF
authors.lastname: Vliegenthart
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
authors.forename: K
authors.initials: K
authors.lastname: Nicolay
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides / Q000378:metabolism; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010042:Ouabain; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D000077285:Rimonabant
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D010042:Ouabain; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide