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

Paula Ortiz-Romero,Gustavo Egea,Alejandro González-Simón,Luis A Pérez-Jurado,Victoria Campuzano

doi:10.3389/fphar.2021.670785

Abstract

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.

Highlights

Williams–Beuren syndrome (WBS, OMIM 194050) is a rare neurodevelopmental disorder with an estimated prevalence of 1 in 7,500–20,000 newborns that is caused by the heterozygous deletion of 26–28 contiguous genes (1.55–1.83 Mb) on chromosome 7q11.23 (Strømme et al, 2002; Bayés et al, 2003)
To identify the molecular causes that could be related to the improvement in certain aspects of the behavioral phenotype in VERCUR-treated animals, we investigated differentially expressed genes (DEGs) by performing an RNA-seq analysis of the cerebral cortex from VERCUR-treated complete deletion (CD) mice versus VEH-treated CD and WT mice
We analyzed the effect of a treatment combining curcumin, the most abundant phenol in turmeric, and verapamil, a widely used medication, on the CD murine model of WBS

Summary

Introduction

Williams–Beuren syndrome (WBS, OMIM 194050) is a rare neurodevelopmental disorder with an estimated prevalence of 1 in 7,500–20,000 newborns that is caused by the heterozygous deletion of 26–28 contiguous genes (1.55–1.83 Mb) on chromosome 7q11.23 (Strømme et al, 2002; Bayés et al, 2003). Together with some cardiovascular features, WBS individuals present mild to moderate intellectual disability, with a mean intelligence quotient (IQ) that ranges between 50 and 60 (Martens et al, 2008). They present a unique cognitive phenotype that includes severe deficits in visuospatial construction and increased sociability, together with preserved linguistic abilities (Bellugi et al, 2000; Doyle et al, 2004). Pharmacological intervention is usually inaccurate and only targeted to treat anxiety (Green et al, 2012; Martens et al, 2012) For this reason, it is interesting to study any potential treatment that might improve the cognitive impairments observed in WBS

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