Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins
Open Access
- 19 February 2020
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (4), 1404
- https://doi.org/10.3390/ijms21041404
Abstract
Epigallocatechin gallate (EGCG) is an inhibitor of DYRK1A, a serine/threonine kinase considered to be a major contributor of cognitive dysfunctions in Down syndrome (DS). Two clinical trials in adult patients with DS have shown the safety and efficacy to improve cognitive phenotypes using commercial green tea extract containing EGCG (45% content). In the present study, we performed a preclinical study using FontUp®, a new nutritional supplement with a chocolate taste specifically formulated for the nutritional needs of patients with DS and enriched with a standardized amount of EGCG in young mice overexpressing Dyrk1A (TgBACDyrk1A). This preparation is differential with previous one used, because its green tea extract has been purified to up 94% EGCG of total catechins. We analyzed the in vitro effect of green tea catechins not only for EGCG, but for others residually contained in FontUp®, on DYRK1A kinase activity. Like EGCG, epicatechin gallate was a noncompetitive inhibitor against ATP, molecular docking computations confirming these results. Oral FontUp® normalized brain and plasma biomarkers deregulated in TgBACDyrk1A, without negative effect on liver and cardiac functions. We compared the bioavailability of EGCG in plasma and brain of mice and have demonstrated that EGCG had well crossed the blood-brain barrier.This publication has 54 references indexed in Scilit:
- PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKaPredictionsJournal of Chemical Theory and Computation, 2011
- Engineering DYRK1A overdosage yields Down syndrome-characteristic cortical splicing aberrationsNeurobiology of Disease, 2010
- Biological actions of green tea catechins on cardiac troponin CBritish Journal of Pharmacology, 2010
- DYRK1A, a Novel Determinant of the Methionine-Homocysteine Cycle in Different Mouse Models Overexpressing this Down-Syndrome-Associated KinasePLOS ONE, 2009
- AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreadingJournal of Computational Chemistry, 2009
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1APLOS ONE, 2009
- The selectivity of protein kinase inhibitors: a further updateBiochemical Journal, 2007
- Tea and cancer prevention: Molecular mechanisms and human relevanceToxicology and Applied Pharmacology, 2007
- The Protein Data BankNucleic Acids Research, 2000