title: Targeting the endocannabinoid system in the amygdala kindling model of temporal lobe epilepsy in mice.
abstract: The endocannabinoid system can be considered as a putative target to affect ictogenesis as well as the generation of a hyperexcitable epileptic network. Therefore, we evaluated the effect of a CB1 receptor agonist (WIN55.212-2) and of an inhibitor of the enzymatic degradation of the endocannabinoid anandamide (fatty acid hydrolase inhibitor URB597) in the amygdala kindling model of temporal lobe epilepsy. Only minor effects on seizure thresholds and seizure parameters without a clear dose-dependency were observed in fully kindled mice. When evaluating the impact on kindling acquisition, WIN55.212-2 significantly delayed the progression of seizure severity. In contrast, URB597 did not affect the development of seizures in the kindling paradigm. Analysis of cell proliferation and neurogenesis during the kindling process revealed that URB597 significantly reduced the number of newborn neurons. These data give first evidence that CB1-receptor activation might render a disease-modifying approach. Future studies are necessary that further analyze the role of CB1 receptors and to confirm the efficacy of CB1-receptor agonists in other models of chronic epilepsy.
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstrasse 16, Munich, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Wendt
authors.forename: Jonna
authors.initials: J
authors.lastname: Soerensen
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000209:etiology* / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008959:Models, Neurological; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D048588:Benzoxazines; D002219:Carbamates; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; 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