title: Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy.
abstract: N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.
authors.affiliation: Department of Health Science, School of Medicine and Surgery, University Magna Graecia of Catanzaro, Viale Europa - Germaneto, 88100 Catanzaro, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Citraro
authors.forename: Emilio
authors.initials: E
authors.lastname: Russo
authors.forename: Francesca
authors.initials: F
authors.lastname: Scicchitano
authors.forename: Clementina M
authors.initials: CM
authors.lastname: van Rijn
authors.forename: Donato
authors.initials: D
authors.lastname: Cosco
authors.forename: Carmen
authors.initials: C
authors.lastname: Avagliano
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Luisa
authors.initials: L
authors.lastname: Gatta
authors.forename: Gilles
authors.initials: G
authors.lastname: van Luijtelaar
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
mesh_terms: D000577:Amides; D000818:Animals; D000927:Anticonvulsants; D001095:Arachidonic Acids / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D063388:Endocannabinoids / Q000494:pharmacology*; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000235:genetics; D004983:Ethanolamines / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology; D007276:Injections, Intraventricular; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000187:drug effects*; D010169:Palmitic Acids / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D000077285:Rimonabant; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000577:Amides; D000927:Anticonvulsants; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D004983:Ethanolamines; C449302:GW 6471; D005989:Glycerides; D010080:Oxazoles; D047493:PPAR alpha; D010169:Palmitic Acids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014443:Tyrosine; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide