Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

Stagni, Fiorenza; Giacomini, Andrea; Emili, Marco; Guidi, Sandra; Ciani, Elisabetta; Bartesaghi, Renata

doi:10.1080/23262133.2016.1270383

Cited by 15 publications

(16 citation statements)

References 30 publications

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“…EGCG has been tested in vitro and in clinical trials, alone or in combination with cognitive training programs (de la Torre et al, ). However, the beneficial effects of EGCG appear largely inconsistent (Stagni et al, ; Stringer, Goodlett, & Roper, ) and other studies are granted to confirm the efficacy of this approach. Another possible pharmacological approach is based on inhibitors of GABA A receptors or other modulators of GABA A ‐mediated transmission, such as NKCC1 (Contestabile, Magara, & Cancedda, ).…”

Section: How To Face the Cognitive Deterioration Of Ds Persons?mentioning

confidence: 99%

Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

et al. 2019

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Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age‐associated disorders much earlier than euploid persons. Furthermore, a series of recent studies have found that DS persons display elevated levels of age biomarkers, thus supporting the notion that DS is a progeroid trait. Nowadays, due to the progressive advancements in social inclusion processes and medical assistance, DS persons live much longer than in the past; therefore, the early‐onset health problems of these persons are becoming an urgent and largely unmet social and medical burden. In particular, the most important ailment of DS persons is the accelerated cognitive decline that starts when they reach about 40 years of age. This decline can be at least in part counteracted by multi‐systemic approaches including early‐onset cognitive training, physical activity, and psychosocial assistance. However, no pharmacological treatment is approved to counteract this decline. According to the most advanced conceptualization of Geroscience, tackling the molecular mechanisms underpinning the aging process should be a smart/feasible strategy to combat and/or delay the great majority of age‐related diseases, including cognitive decline. We think that a debate is needed urgently on if (and how) this strategy could be integrated in protocols to face DS‐associated dementia and overall unhealthy aging. In particular we propose that, on the basis of data obtained in different clinical settings, metformin is a promising candidate that could be exploited to counteract cognitive decline in DS.

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Section: How To Face the Cognitive Deterioration Of Ds Persons?mentioning

confidence: 99%

Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

et al. 2019

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“…Several studies that have administered EGCG or EGCG‐containing supplements to transgenic Dyrk1a or Ts65Dn mice have reported improved behavioral outcomes [Table , also see (Stagni et al. )]. The amount of heterogeneity among studies across multiple variables is striking, involving different mouse models, ages, doses and composition of the EGCG treatment, as well as different behavioral tasks and outcomes.…”

Section: Heterogeneity In Behavioral Outcomes After Egcg and Egcg‐conmentioning

confidence: 99%

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

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“…There is no remedy for Down syndrome, yet a recent clinical study [ 7 ] provides a glimmer of hope that EGCG might alleviate its symptoms. Although results presented in a Phase 2 clinical trial for individuals with DS are promising [ 7 ], there are other studies claiming no improvement [ 81 , 82 , 89 , 90 ] or presenting unwanted side effects [ 89 ] in the mouse models of DS [ 93 , 94 , 95 , 96 ] when EGCG was administrated.…”

Section: Discussionmentioning

confidence: 99%

Can EGCG Alleviate Symptoms of Down Syndrome by Altering Proteolytic Activity?

Wyganowska‐Świątkowska

Matthews‐Kozanecka

Borysewicz−Lewicka

et al. 2018

IJMS

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Down syndrome (DS), also known as “trisomy 21”, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. Silencing these extra genes is beyond existing technology and seems to be impractical. A number of pharmacologic options have been proposed to change the quality of life and lifespan of individuals with DS. It was reported that treatment with epigallocatechin gallate (EGCG) improves cognitive performance in animal models and in humans, suggesting that EGCG may alleviate symptoms of DS. Traditionally, EGCG has been associated with the ability to reduce dual specificity tyrosine phosphorylation regulated kinase 1A activity, which is overexpressed in trisomy 21. Based on the data available in the literature, we propose an additional way in which EGCG might affect trisomy 21—namely by modifying the proteolytic activity of the enzymes involved. It is known that, in Down syndrome, the nerve growth factor (NGF) metabolic pathway is altered: first by downregulating tissue plasminogen activator (tPA) that activates plasminogen to plasmin, an enzyme converting proNGF to mature NGF; secondly, overexpression of metalloproteinase 9 (MMP-9) further degrades NGF, lowering the amount of mature NGF. EGCG inhibits MMP-9, thus protecting NGF. Urokinase (uPA) and tPA are activators of plasminogen, and uPA is inhibited by EGCG, but regardless of their structural similarity tPA is not inhibited. In this review, we describe mechanisms of proteolytic enzymes (MMP-9 and plasminogen activation system), their role in Down syndrome, their inhibition by EGCG, possible degradation of this polyphenol and the ability of EGCG and its degradation products to cross the blood–brain barrier. We conclude that known data accumulated so far provide promising evidence of MMP-9 inhibition by EGCG in the brain, which could slow down the abnormal degradation of NGF.

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Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

Cited by 15 publications

References 30 publications

Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Can EGCG Alleviate Symptoms of Down Syndrome by Altering Proteolytic Activity?

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