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

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.

Formulation and Optimization of Nanospanlastics for Improving the Bioavailability of Green Tea Epigallocatechin Gallate

“…Group A administered EGCG-loaded spanlastic dispersion, group B administered the corresponding niosomal dispersion, and group C administered EGCG dispersion. Each dispersion, equivalent to 50 mg/kg of EGCG, [93,94], was administered orally by a gavage tube. Blood samples were withdrawn, from the tail vein, into heparin-containing tubes, immediately prior to dosing (zero time) and then after administration of EGCG formulations at 0.5, 1, 2, 3, 4, 8, 12, and 24 h. Different blood samples were centrifuged at 15,000 rpm for 10 min and 100 µL plasma samples were then collected, vortex-mixed for 1 min, and centrifuged at 5000 rpm for 5 min.…”

Behavioral Phenotyping for Down Syndrome in Mice

“…6, upper left panel: main effect of day [p < .001]; day × genotype interaction [p = .004]). In contrast, our recent report (Goodlett et al, 2020) assessed male Ts65Dn (n = 10) and euploid (n = 12) mice chronically treated via daily gavage beginning on postnatal day 42 and tested in the MCSF on postnatal days 49 and 50. As shown in Figure 6, upper right panel, both groups given PBS control gavage treatments showed modest increases in activity on the second day (main effect of day [p = .022]) that did not approach levels seen in the fluid consumption study.…”

“…There is evidence that early Stringer et al (2017), in which treatments were administered through the drinking water. The right panels show data reported in Goodlett et al (2020) in which treatments were administered via daily gavage. Note the different patterns of outcomes with the two different treatment conditions, particularly the more limited increase in activity on the second day in the gavage groups compared to fluid-consuming groups, and the significant reduction in risk-taking behavior on both days in the trisomic mice given the control gavage treatments.…”

Epigallocatechin-3-Gallate Plus Omega-3 Restores the Mitochondrial Complex I and F0F1-ATP Synthase Activities in PBMCs of Young Children with Down Syndrome: A Pilot Study of Safety and Efficacy

“…Some questions remain to be solved such as the most appropriate mode of delivery, the quality of EGCG (green tea extracts or pure EGCG), the combination of EGCG with other nutraceuticals and the dose-response relationship. At this regard, the lack of advantageous therapeutic behavioral effects and potentially detrimental skeletal outcomes of high EGCG dose have been reported in Ts65Dn mice [ 60 , 61 ]. Another study showed that even using a pure stabilized EGCG in the concentrations producing therapeutic effects on skeletal phenotypes, EGCG failed to improve cognitive phenotypes in adolescent DS mice [ 62 ].…”