title: L-type calcium channel mediates anticonvulsant effect of cannabinoids in acute and chronic murine models of seizure.
abstract: The anticonvulsant activities of cannabinoid compounds have been shown in various models of seizure and epilepsy. At least, part of antiseizure effects of cannabinoid compounds is mediated through calcium (Ca(2+)) channels. The L-type Ca(2+) channels have been shown to be important in various epilepsy models. However, there is no data regarding the role of L-type Ca(2+) channels in protective action of cannabinoids on acute and chronic models of seizure. In this study, the effects of cannabinoid compounds and L-type Ca(2+) channels blockers, either alone or in combination were investigated using acute model of pentylenetetrazole (PTZ)-induced seizure in mice and chronic model electrical kindling of amygdala in rats. Pretreatment of mice with both cannabinoid CB1 receptor agonist arachidonyl-2'-chloroethylamide (ACEA) and endocannabinoid degradating enzyme inhibitor cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) produced a protective effect against PTZ-induced seizure. Administration of various doses of the two L-type Ca(2+) channel blockers verapamil and diltiazem did not alter PTZ-induced seizure threshold. However, co-administration of verapamil and either ACEA or URB597 attenuated the protective effect of cannabinoid compounds against PTZ-induced seizure. Also, pretreatment of mice with diltiazem blocked the anticonvulsant activity of both ACEA and URB597. Moreover, (R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55,212-2), the non-selective cannabinoid CB1 and CB2 receptor agonist showed anticonvulsant effect in amygdala-kindled rats. However, co-administration of WIN55,212-2 and verapamil attenuated the protective properties of WIN55,212-2. Our results showed that the anticonvulsant activity of cannabinoid compounds is mediated, at least in part, by L-type Ca(2+) channels in these two models of convulsion and epilepsy.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave., P.O. Box: 14155-6153, 1996835113, Tehran, Iran. naderi@sbmu.ac.ir
authors.forename: Nima
authors.initials: N
authors.lastname: Naderi
authors.forename: Leila
authors.initials: L
authors.lastname: Ahmad-Molaei
authors.forename: Ali
authors.initials: A
authors.lastname: Mazar-Atabaki
authors.forename: Abdolaziz
authors.initials: A
authors.lastname: Ronaghi
authors.forename: Zahra
authors.initials: Z
authors.lastname: Shirazi-zand
authors.forename: Seyed Mehrdad
authors.initials: SM
authors.lastname: Motiei-Langroudi
authors.forename: Somayeh
authors.initials: S
authors.lastname: Eslahkar
mesh_terms: D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates / Q000494:pharmacology; D002908:Chronic Disease; D004110:Diltiazem / Q000494:pharmacology; D004195:Disease Models, Animal; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; D048588:Benzoxazines; D020746:Calcium Channels, L-Type; D002186:Cannabinoids; D002219:Carbamates; D009025:Morpholines; D009281:Naphthalenes; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014700:Verapamil; D004110:Diltiazem