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

Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.

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

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.