Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Cieuta‐Walti, Cécile; Cuenca‐Royo, Aida; Langohr, Klaus; Rakic, Claire; López-Vílchez, Ma Ángeles; Lirio, Julián; Leguina, Domingo González-Lamuño; González, Teresa Bermejo; García, Jordi García; Roure, Maria Rimblas; Aldea-Perona, Ana; Forcano, Laura; Gomis-González, María; Videla, Sebastián; Lacaille, Florence; Ravel, Aimé; Mircher, Clotilde; Walti, Hervé; Janel, Nathalie; Dairou, Julien; Lévy, Marilyne; Durand, Sophie; Dierssen, Mara; Sacco, Silvia; Fornell, Rafael de la Torre

doi:10.1016/j.gim.2022.06.011

Cited by 17 publications

(15 citation statements)

References 15 publications

(26 reference statements)

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“…EGCG is a polyphenolic, flavonoid antioxidant found in a number of plants, such as green tea ( Camellia sinensis ). , Although dozens of molecular targets have been described for EGCG, it has been used as a DYRK1A inhibitor (either as a purified compound or as a green tea extract) in numerous enzymatic, cellular, and animal studies, − as well as clinical trials in people with DS. , Its DYRK1A inhibitory activity was reported as modest: IC 50 of 330 nM, 232 nM (more potent analogues were synthesized in ref ). We found IC 50 values of 491, 714, 72, and 368 nM for DYRK1A, DYRK1B, CLK1, and CLK4, respectively, but also similar values for CDK5/p25 and CK1ε (431 and 365 nM).…”

Section: Discussionmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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Section: Discussionmentioning

confidence: 99%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…A significant number of clinical trials have been conducted on the EGCG polyphenolic flavonoid component of green tea. An examination of a selection of these trials [ 265 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 ] amply demonstrate the diverse biological properties of EGCG and its potential therapeutic applications. EGCG can potentially improve cognition in children with Down syndrome [ 276 ].…”

Section: Flavonoid Clinical Trialsmentioning

confidence: 99%

“…An examination of a selection of these trials [ 265 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 ] amply demonstrate the diverse biological properties of EGCG and its potential therapeutic applications. EGCG can potentially improve cognition in children with Down syndrome [ 276 ]. EGCG prevents skin dermatitis in skin cancer patients receiving radiotherapy [ 277 ], and topical application of EGCG improves the treatment of vitilago [ 278 ].…”

Section: Flavonoid Clinical Trialsmentioning

confidence: 99%

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Melrose

2023

Antioxidants

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Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

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“…15 Recently, it was also proven to be safe in children with Down syndrome. 71 Interestingly, not only does epigallocatechin-3-gallate inhibit DYRK1A, but it also targets key postsynaptic and plasticity-related pathways 72,73 and inhibits CBS, 74 a major H 2 S-generating enzyme, potentially contributing to ameliorating cognition in Down syndrome. 75 However, given that DYRK1A function is dosage dependent, an excessive long-term inhibition may be deleterious, especially during development.…”

Section: Disease-modifying Therapy: Chromosomal Inactivation Versus G...mentioning

confidence: 99%

“…Natural DYRK1A inhibitors include epigallocatechin‐3‐gallate, which in phase II clinical trials showed target engagement and moderate effects on cognition and adaptive behaviour, alongside improved brain functional connectivity 15 . Recently, it was also proven to be safe in children with Down syndrome 71 . Interestingly, not only does epigallocatechin‐3‐gallate inhibit DYRK1A, but it also targets key postsynaptic and plasticity‐related pathways 72,73 and inhibits CBS, 74 a major H 2 S‐generating enzyme, potentially contributing to ameliorating cognition in Down syndrome 75 .…”

Section: From Symptomatic To Disease‐modifying Therapymentioning

confidence: 99%

State‐of‐the‐art therapy for Down syndrome

Lorenzón

Musoles-Lleó

Turrisi

et al. 2023

Develop Med Child Neuro

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Down syndrome is the most common chromosomal disorder, caused by a third copy of all or part of chromosome 21 (HSA21), and the most complex and prevalent genetic cause of intellectual disability. 1 It is a chronic, multifactorial disorder that affects brain development and function, impairing cognition and adaptive behaviour. 2 Moreover, Down syndrome co-occurs with autism and epilepsy and is considered a genetic form of Alzheimer disease. 3 In addition, individuals with Down syndrome have a high prevalence of endocrine disorders and obesity, leading to type 2 diabetes, insulin resistance, and neuroinflammation, 4 which, in turn, contribute to cognitive deficits.In the last decade, an important effort was made to better understand the pathogenetic mechanisms involved in Down

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Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Cited by 17 publications

References 15 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

State‐of‐the‐art therapy for Down syndrome

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