IUPUI Department of Psychology, 402 North Blackford Street, LD 124, Indianapolis, IN, 46202-3275, USA.
IUPUI Department of Biology, 723 West Michigan Street; SL 306, Indianapolis, IN, 46202-3275, USA.
Sci Rep. 2020 Jun 26;10(1):10426. doi: 10.1038/s41598-020-67133-z.
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.
没食子酸表没食子儿茶素酯（EGCG）是唐氏综合征（DS）表型的候选治疗药物，其基于体外抑制 DYRK1A，该基因是 21 号三体（Ts21）的三倍产物。绿茶提取物中含有的 EGCG 可改善 DS 小鼠模型和 Ts21 人类患者的一些认知和行为结果。相比之下，在 DS 小鼠模型中，用纯 EGCG 治疗并未改善神经行为表型。本研究检验了以下假说，即通过口服灌胃给予 200mg/kg/天的纯 EGCG 可改善 Ts65Dn DS 小鼠模型的神经行为和骨骼表型。灌胃后，三体小鼠的血清 EGCG 水平明显高于二倍体小鼠。三周的每日 EGCG 灌胃处理导致二倍体和三体小鼠均出现生长缺陷。与载体处理相比，EGCG 并未显著改善 Ts65Dn 小鼠在多元同心方场、平衡木或 Morris 水迷宫任务中的行为表现，但降低了游泳速度。此外，EGCG 导致 Ts65Dn 小鼠皮质骨结构和强度降低。这些结果未能支持 EGCG 的治疗潜力，并且对生长和骨骼表型的有害影响强调了在 DS 中作为干预措施使用高剂量 EGCG 补充剂需要谨慎。
