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, Galera López, Lorena, Ortiz Romero, Paula, Llorente Ovejero, Alberto, de Los Reyes Ramírez, Lucía, Bengoetxea de Tena, Iker, Garcia Elias, Anna, Mas Stachurska, Aleksandra, Reixachs Solé, Marina, Pastor, Antoni, de la Torre, Rafael, Maldonado, Rafael, 1961-, Benito, Begoña, Eyras, Eduardo, Rodríguez Puertas, Rafael, Campuzano Uceda, María Victoria, Ozaita, Andres
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/189977
Acesso em linha:https://hdl.handle.net/2445/189977
Access Level:Acceso aberto
Palavra-chave:Cànnabis
Síndrome de Williams
Persones amb discapacitat mental
Ratolins
Cannabis
Williams syndrome
People with mental disabilities
Mice
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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