Biology subjects

Ortiz-Romero, P.

Publications and source records attributed to Ortiz-Romero, P..

4 recordsLinked to original sources

bioRxiv2022

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

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder with hallmarks in the cardiovascular manifestations and no well-defined therapeutic strategies. We investigated the progression of cardiovascular phenotype present in CD (complete deletion) mice, a murine model of WBS, after chronic treatment with curcumin and verapamil, both compounds with positive effects on related pathologies. Treatment was administered orally dissolved in drinking water. After measuring "in vivo" systolic blood pressure, aortic and left ventricular myocardium were histological and molecular analysed to determine the effects of treatment and its underlying mechanism in CD mice. We observed upregulated xanthine oxidoreductase (XOR) expression in both aortic and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as example of byproduct-mediated oxidative stress damage, indicating of XOR-generated oxidative stress impact on the pathophysiology of cardiovascular manifestations in WBS, and suggesting that the inhibition of XOR and/or oxidative stress damage could help to ameliorate the severe cardiovascular injuries presented in WBS.

genetics↗

bioRxiv2021

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 available treatments to 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 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 sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac 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.

animal behavior and cognition↗

bioRxiv2021

Verapamil/Curcumin treatment attenuates the behavioral alterations observed in Williams 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 currently are not any effective treatments. We investigated the progression of behavioral deficits present in CD (complete deletion) mice, a rodent model of WBS, 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 in CD mice. Behavioral improvement correlates with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation with the control of synaptic transmission. Moreover, CD mice showed an increased activated microglia density in different brain regions, which was prevented by treatment. Therefore, results show that treatment prevented behavioral deficits by recovering altered gene expression in cortex of CD mice, reducing activated microglia and normalizing Bdnf expression levels. 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.

animal behavior and cognition↗

bioRxiv2020

Chlorzoxazone, A BKCa Channel Agonist, Rescues The Pathological Phenotypes Of Williams-Beuren Syndrome In A Preclinical Model

Williams-Beuren syndrome (WBS) is a rare developmental disorder caused by the deletion of a 1.5 Mb region in chromosome 7 (7q11.23). WBS has been recently modelled by a mutant mouse line having a complete deletion (CD) of the equivalent locus on mouse chromosome 5, thus resembling the genetic defect found in WBS patients. CD mice have been shown to have physical and neurobehavioral abnormalities that recapitulate most of the symptoms associated with human WBS, including cardiovascular, motor, social, emotional and sensory alterations. This model has been largely used to investigate the etiopathological mechanisms of WBS; nonetheless, pharmacological therapies for this syndrome have not been identified yet. Here we propose a novel treatment for WBS, chlorzoxazone (CHLOR), i.e., a molecule targeting calcium-activated large conductance potassium (BKCa) channels, since a reduction in the expression of these channels has been recently described in neurons from WBS patients, as well as in other rare developmental pathologies. Our results demonstrate both the acute and chronic effects of CHLOR on some major pathological phenotypes of CD mice, including several behavioural alterations and cardiac hypertrophy. We conclude that BKCa channels are a therapeutic target of high potential for clinical applications and are likely to play a key role in the etiopathology of WBS.

neuroscience↗