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

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.

Curcumin combined with verapamil improve cardiovascular phenotype of a Williams-Beuren Syndrome mice model reducing oxidative stress

“…The treatment was administered following the protocols previously used by the group (Ortiz-Romero et al, 2021). Vehicle control group (VEH) consisted of WT and CD mice drinking water with 1% DMSO.…”

“…We previously reported that only the combined (CURVER) and no the single treatment with CUR and VER significantly improved the cognitive phenotype of CD mice (Ortiz-Romero et al, 2021). Subsequently, we next aim was to evaluate if the combinatorial treatment could represent an effective pharmacological strategy to treat cardiovascular alterations in CD mice, as well as, the role of the XOR as another important source of oxidative stress in WBS .…”

“…Severe SVAS can lead to cardiac hypertrophy and increases the risk of complications such as stroke and sudden death (Wessel et al, 2004; Collins, 2018).The complete deletion (CD) mouse model of WBS presents a cardiovascular phenotype very similar to that seen in patients with presence of aortic stenosis, hypercardiopathy and hyperthensión (Segura-Puimedon et al, 2014; Jiménez-Altayó et al, 2020). Morever this mouse model has been used to assay potential therapeutic interventions (Ortiz-Romero et al, 2018, 2021).…”

The Combined Treatment of Curcumin with Verapamil Ameliorates the Cardiovascular Pathology in a Williams–Beuren Syndrome Mouse Model

“…The complete deletion (CD) mouse model, carrying the most common deletion found in WBS patients (from Gtf2i to Fkbp6 ), presents a pathological cardiovascular phenotype very similar to that seen in patients with SVAS, hypertrophic cardiopathy and hypertension [ 4 , 5 ]. Moreover, the CD mouse model is the most suitable for assaying potential new therapeutic interventions [ 6 , 7 ].…”

“…We previously reported that only the combined (CURVER) and not a single treatment (CUR or VER) significantly improved the cognitive dysfunction of CD mice [ 6 ]. We then evaluated whether the combinatorial treatment could also represent an effective pharmacological strategy to treat cardiovascular alterations in CD mice, as well as studying the role of XOR as it is an important source of oxidative stress in the cardiovascular system.…”