Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

Frontiers in Pharmacology

Victoria Campuzano¹  Paula Ortiz-Romero²  Alejandro González-Simón²  Gustavo Egea³  Luis A. Pérez-Jurado⁴ 

[1] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain;Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain;Institut d’Investigacions Biomèdiques August Pi I Sunyer, IDIBAPS-UB, Barcelona, Spain;Servei de Genètica, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain;Unitat de Genètica, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain;

关键词: Williams–Beuren syndrome;    curcumin;    verapamil;    mice;    activated glia;    behavior;   

DOI  :  10.3389/fphar.2021.670785

来源: DOAJ

【 摘 要 】

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

【 授权许可】

Unknown