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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.
Highlights
DYRK1A is a dual-specificity protein kinase which gene is located on 21q22.2 of human chromosome 21 [1] overexpressed in Down syndrome (DS)
We first monitored the amount of polyphenols in the FontUp® formulation by high performance liquid chromatography (HPLC) coupled with diode array detector (DAD)
We found increased plasma hcy concentrations in TgBACDyrk1A mice with the D2 dose (Figure 3A), without statistical effect for plasma ALT levels (Figure 3B)
Summary
DYRK1A (dual-specificity tyrosine phosphorylation-related kinase 1A) is a dual-specificity protein kinase which gene is located on 21q22.2 of human chromosome 21 [1] overexpressed in Down syndrome (DS). Phenotypic characteristics are complex and variable, but reduced learning and memory capacities are common to all individuals with DS [2]. They exhibit impaired development of the nervous system and a delay in cognitive development leading to intellectual disability [2]. A large number of studies have evaluated the effect of normalizing the DYRK1A expression and/or kinase activity on the learning and memory capacities of DS mouse models [4]. The green tea catechin, epigallocatechin-3-gallate (EGCG) is the most used in preclinical studies, considering the safety of the molecule and the interesting potency to inhibit DYRK1A activity with IC50 of 330 nM [5]. Most of the DYRK1A inhibition studies with EGCG treatment showed some beneficial effects [6,7,8,9,10,11,12,13,14,15]
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