Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-alpha receptor activation in a genetic model of absence epilepsy

作者：Citraro Rita; Russo Emilio; Scicchitano Francesca; van Rijn Clementina M; Cosco Donato; Avagliano Carmen; Russo Roberto; D' Agostino Giuseppe; Petrosino Stefania; Guida Francesca; Gatta Luisa; van Luijtelaar Gilles; Maione Sabatino; Di Marzo Vincenzo; Calignano Antonio; De Sarro Giovambattista^*

来源：Neuropharmacology, 2013, 69: 115-126.

DOI：10.1016/j.neuropharm.2012.11.017

• Endocannabinoids
• Absence seizures
• SWDs
• Anandamide
• SR141716
• GW6471

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-alpha). 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-alpha in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-alpha antagonist (GW6471) and a synthetic CBI 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 CBI receptors and PPAR-alpha. 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%26apos;s effects whereas it did not modify AEA%26apos;s effects. %26lt;br%26gt;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-alpha. and indirect activation of CBI receptors. %26lt;br%26gt;This article is part of the Special Issue entitled %26apos;New Targets and Approaches to the Treatment of Epilepsy%26apos;.

• 出版日期2013-6