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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

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

Rita Citraro, Emilio Russo, Antonio Leo, Roberto Russo, Carmen Avagliano, Michele Navarra, Antonio Calignano, Giovambattista De Sarro

Eur J Pharmacol. 2016 Nov 15;791:523-534.

PMID: 27663280

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP502486897	NIDA-41020		502486-89-7	Price

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