gw-6471 and anandamide

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'.

Topics: Amides; Animals; Anticonvulsants; Arachidonic Acids; Calcium Channel Blockers; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Electroencephalography; Endocannabinoids; Epilepsy, Absence; Ethanolamines; Glycerides; Injections, Intraventricular; Lipid Metabolism; Male; Oxazoles; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Tyrosine

Endocannabinoids (anandamide and 2-AG) are relevant modulators of appetite and energy expenditure through their action on cannabinoid CB(1) receptors. The actions of anandamide on feeding behavior are dependent both, on the anatomical location of CB(1) receptors (central nervous system versus peripheral tissues) and the feeding status. Anandamide uptake into cells, prior to its degradation by specific enzymatic systems, is a necessary step for the regulation of its extracellular levels. The present study explores the route and feeding stimulus dependency of the effects of the anandamide uptake blocker AM404. Peripherally, AM404 reduced feeding in partially satiated animals through a PPARα-independent mechanism, but not in food deprived ones. When AM404 was injected into the cerebral ventricles of food deprived rats, it resulted in hyperphagia that was antagonized by the cannabinoid receptor inverse agonist SR141716A. These results support the multimodal action of endocannabinoid signaling in feeding regulation, which depends on the anatomical site and the feeding status of the animal.

Topics: Animals; Arachidonic Acids; Eating; Endocannabinoids; Energy Intake; Feeding Behavior; Food Deprivation; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Mice, Knockout; Nutritional Status; Oxazoles; Piperidines; Polyunsaturated Alkamides; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Satiation; Tyrosine