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Eur J Pharmacol. 2016 Nov 15;791:523-534. doi: 10.1016/j.ejphar.2016.09.029. Epub 2016 Sep 20.

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.

Author information

1
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
2
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
3
Department of Experimental Pharmacology, University of Messina, Messina, Italy.
4
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. Electronic address: desarro@unicz.it.

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.

KEYWORDS:

Antiepileptic drugs; Audiogenic seizure model; Cannabinoid compounds; Drug interaction; PEA; PPAR-α receptors

PMID:
27663280
DOI:
10.1016/j.ejphar.2016.09.029
[Indexed for MEDLINE]

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