Volume 69, June 2013, Pages 115–126
New Targets and Approaches to the Treatment of Epilepsy
Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy
- Rita Citraroa, 1,
- Emilio Russoa, 1,
- Francesca Scicchitanoa,
- Clementina M. van Rijnb,
- Donato Coscoa,
- Carmen Avaglianoc,
- Roberto Russoc,
- Giuseppe D’Agostinoc,
- Stefania Petrosinod,
- Francesca Guidae,
- Luisa Gattae,
- Gilles van Luijtelaarb,
- Sabatino Maionee,
- Vincenzo Di Marzod,
- Antonio Calignanoc,
- Giovambattista De Sarroa,
, 
- a Department of Health Science, School of Medicine and Surgery, University “Magna Graecia” of Catanzaro, Viale Europa – Germaneto, 88100 Catanzaro, Italy
- b Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, The Netherlands
- c Department of Experimental Pharmacology, University of Naples “Federico II”, Naples, Italy
- d Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio nazionale delle Ricerche, Pozzuoli (NA), Italy
- e Endocannabinoid Research Group, Department of Experimental Medicine, Division of Pharmacology “L. Donatelli”, Second University of Naples, Italy
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’.
Highlights
Keywords
Endocannabinoids;- Absence seizures;
- SWDs;
- Anandamide;
- SR141716;
- GW6471
Figures and tables from this article:
- Fig. 1. Time-course of acute PEA administration against absence seizures (SWDs) in WAG/Rij rats. A and B: PEA’s effects after intraperitoneal (i.p.) administration on both SWDs’ number and duration. C and D: PEA’s effects after intracerebroventricular (i.c.v.) administration on both SWDs’ number and duration. Data values are means ± SEM for 30 min epochs. PEA = N-palmitoylethanolamine; SWD = spike-wave discharge; Vehicle = vehicle treated control group.
- Fig. 2. Effects of acute i.c.v. administration of anandamide (AEA) in WAG/Rij rats. Plots show time- and dose-dependent effects of AEA on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 3. Effects of acute i.c.v. administration of SR141716 in WAG/Rij rats. Plots show time- and dose-dependent effects of SR141716 on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 4. Effects of acute i.c.v. administration of GW6471 in WAG/Rij rats. Plots show time- and dose-dependent effects of GW6471 on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 5. Blocking effects of SR141716 administered 30 min before PEA on its anti-absence properties in WAG/Rij rats. Plots show time- and dose-dependent effects of SR141716 in combination with various doses of PEA on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 6. Blocking effects of GW6471 administered 30 min before PEA on its anti-absence properties in WAG/Rij rats. Plots show time- and dose-dependent effects of GW6471 in combination with PEA (3 μg/2 μl) on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 7. Blocking effects of SR141716 administered 30 min before AEA on its anti-absence properties in WAG/Rij rats. Plots show time- and dose-dependent effects of SR141716 in combination with AEA (3 μg/2 μl) on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Fig. 8. Lack of effects of GW6471 administered 30 min before AEA on its anti-absence properties in WAG/Rij rats. Plots show time- and dose-dependent effects of GW6471 in combination with AEA (3 μg/2 μl) on the number (A) and duration (B) of epileptic SWDs. Data values are means ± SEM for 30 min epochs. Vehicle = vehicle treated control group.
- Table 1. Tissue concentrations of AEA, 2-AG and PEA in WAG/Rij, ACI and Wistar rats.
- Values represent mean ± SEM expressed in nmols per gram of wet tissue extracted. * = P < 0.05 vs. corresponding value in ACI rats; ° = P < 0.05 vs. corresponding value in Wistar rats; # = P < 0.05 vs. corresponding value at 2 months of age of the same strain.
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- Corresponding author. Tel.: +39 (0)961 3694191; fax: +39 (0)961 3694192.
- 1
- Equally contributed to the manuscript.
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