Citraro, R., Russo, E., Leo, A., Russo, R., Avagliano, C., Navarra, M., Calignano, A., De Sarro, G.
Pharmacokinetic-pharmacodynamic influence of N-palmitoylethanolamine, arachidonyl-2′-chloroethylamide and WIN 55,212-2 on the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice
(2016) European Journal of Pharmacology, 791, pp. 523-534.
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988628599&partnerID=40&md5=92f0535899da7f443571a42939ff136d
DOI: 10.1016/j.ejphar.2016.09.029
AFFILIATIONS: Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University “Magna Graecia” of Catanzaro, Italy;
Department of Pharmacy, University of Naples “Federico II”Naples, Italy;
Department of Experimental Pharmacology, University of MessinaMessina, Italy
ABSTRACT: We evaluated the effects of ACEA (selective cannabinoid (CB)1 receptor agonist), WIN 55,212-2 mesylate (WIN; non-selective CB1 and CB2 receptor agonist) and N-palmitoylethanolamine (PEA; an endogenous fatty acid of ethanolamide) in DBA/2 mice, a genetic model of reflex audiogenic epilepsy. PEA, ACEA or WIN intraperitoneal (i.p.) administration decreased the severity of tonic-clonic seizures. We also studied the effects of PEA, WIN or ACEA after co-administration with NIDA-41020 (CB1 receptor antagonist) or GW6471 (PPAR-α antagonist) and compared the effects of WIN, ACEA and PEA in order to clarify their mechanisms of action. PEA has anticonvulsant features in DBA/2 mice mainly through PPAR-α and likely indirectly on CB1 receptors, whereas ACEA and WIN act through CB1 receptors. The co-administration of ineffective doses of ACEA, PEA and WIN with some antiepileptic drugs (AEDs) was examined in order to identify potential pharmacological interactions in DBA/2 mice. We found that PEA, ACEA and WIN co-administration potentiated the efficacy of carbamazepine, diazepam, felbamate, gabapentin, phenobarbital, topiramate and valproate and PEA only also that of oxcarbazepine and lamotrigine whereas, their co-administration with levetiracetam and phenytoin did not have effects. PEA, ACEA or WIN administration did not significantly influence the total plasma and brain levels of AEDs; therefore, it can be concluded that the observed potentiation was only of pharmacodynamic nature. In conclusion, PEA, ACEA and WIN show anticonvulsant effects in DBA/2 mice and potentiate the effects several AEDs suggesting a possible therapeutic relevance of these drugs and their mechanisms of action. © 2016
AUTHOR KEYWORDS: Antiepileptic drugs; Audiogenic seizure model; Cannabinoid compounds; Drug interaction; PEA; PPAR-α receptors
CORRESPONDENCE ADDRESS: De Sarro, G.; Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University “Magna Graecia” of CatanzaroItaly; email: desarro@unicz.it
DOCUMENT TYPE: Article
