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.
We evaluated the effects of ACEA (selective cannabinoid (CB)1receptor agonist), WIN 55,212-2 mesylate (WIN; non-selective CB1and CB2receptor 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 (CB1receptor 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 CB1receptors, whereas ACEA and WIN act through CB1receptors. 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.
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
Rita
R
Citraro
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
Emilio
E
Russo
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy.
Antonio
A
Leo
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
Roberto
R
Russo
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
Carmen
C
Avagliano
Department of Experimental Pharmacology, University of Messina, Messina, Italy.
Michele
M
Navarra
Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
Antonio
A
Calignano
Science of Health Department, Clinical Pharmacology Unit, School of Medicine, University "Magna Graecia" of Catanzaro, Italy. Electronic address: desarro@unicz.it.
Giovambattista
G
De Sarro
D000577:Amides; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001095:Arachidonic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D020195:Epilepsy, Reflex / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010169:Palmitic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000577:Amides; D000927:Anticonvulsants; D001095:Arachidonic Acids; D048588:Benzoxazines; D004983:Ethanolamines; D009025:Morpholines; D009281:Naphthalenes; D010169:Palmitic Acids; C119325:arachidonyl-2-chloroethylamide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C005958:palmidrol
Antiepileptic drugs; Audiogenic seizure model; Cannabinoid compounds; Drug interaction; PEA; PPAR-α receptors