Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice

Charles R Goodlett,Jonathan Lacombe,Joseph M Wallace,Randall J Roper,Megan Stringer,Roshni Patel

doi:10.1038/s41598-020-67133-z

Charles R Goodlett, Jonathan Lacombe + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-67133-z

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Abstract

Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS.

Highlights

Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea, has been hypothesized to reduce the risk or pathogenesis of several neurodegenerative and cardiovascular diseases, as well as cancer[1,2,3,4]
Preclinical evaluation of effects of consuming EGCG-containing green tea extracts on Down syndrome (DS) phenotypes have been assessed in DS mouse models, including Ts65Dn mice that are trisomic for approximately half of the genes found in three copies in Trisomy 21 (Ts21) and mice that are transgenic for Dyrk1a (Table 1)
Studies describing behavioral improvements after administrations of green tea extracts report EGCG doses ranging from ~40 to ~200 mg/kg/day[12,20,54]

Summary

Introduction

Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea, has been hypothesized to reduce the risk or pathogenesis of several neurodegenerative and cardiovascular diseases, as well as cancer[1,2,3,4]. The hypothesis that trisomic DYRK1A is a major contributor to DS phenotypes[17,18] and the demonstration that EGCG inhibits DYRK1A activity in vitro has fueled enthusiasm for the hypothesis that EGCG and green tea extracts could be an effective nutraceutical therapy for DS19. Preclinical evaluation of effects of consuming EGCG-containing green tea extracts on DS phenotypes have been assessed in DS mouse models, including Ts65Dn mice that are trisomic for approximately half of the genes found in three copies in Ts21 and mice that are transgenic for Dyrk1a (Table 1). A three-month treatment of green tea extract (45% EGCG, 9 mg/kg/day EGCG) improved performance on a subset of measures on a battery of cognitive tests, including visual recognition memory[20].

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