Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly amelio...

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Detalhes bibliográficos
Autores: Navarro Romero, Alba, 1990-, Galera López, Lorena, 1993-, Ortiz Romero, Paula, 1994-, Llorente-Ovejero, Alberto, Los Reyes-Ramírez, Lucía de, Bengoetxea de Tena, Iker, Garcia-Elias Heras, Anna, Mas Stachurska, Aleksandra, Reixachs i Solé, Marina, Pastor, Antonio, Torre Fornell, Rafael de la, Maldonado, Rafael, 1961-, Benito Villabriga, Begoña, Eyras Jiménez, Eduardo, Rodríguez-Puertas, Rafael, Campuzano Uceda, María Victoria, Ozaita Mintegui, Andrés, 1969-
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/54885
Acesso em linha:http://hdl.handle.net/10230/54885
http://dx.doi.org/10.7554/eLife.72560
Access Level:acceso abierto
Palavra-chave:Williams–Beuren syndrome
Cannabinoid type-1 receptor
Endocannabinoid system
Intellectual disability
Medicine
Mouse
Descrição
Resumo:Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

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