Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial

Xiong, Chengjie; Maaß, Sylvia; Schuberth, Madeleine; Giese, Armin; Oertel, Wolfgang H.; Poewe, Werner; Trenkwalder, Claudia; Wenning, Gregor K.; Mansmann, Ulrich; Südmeyer, Martin; Eggert, Karla; Mollenhauer, Brit; Lipp, Axel; Löhle, Matthias; Claßen, Joseph; Münchau, Alexander; Kassubek, Jan; Gandor, Florin; Berg, Daniela; Egert-Schwender, Silvia; Eberhardt, Cornelia; Paul, Friedemann; Bötzel, Kai; Ertl‐Wagner, Birgit; Huppertz, Hans‐Jürgen; Ricard, Ingrid; Höglinger, Günter U.; André, Élisabeth; Blankenstein, Christiane; Canelo, Monica; Düring, Marco; Ebentheuer, Jens; Fricke, Christopher; Gerbes, Alexander L.; Groiss, Stefan Jun; Gruber, Doreen; Hartmann, Christian; Kirchner, Thomas; Kroneberg, Daniel; Kunz, Martin; Lorenzl, Stefan; Moldovan, Alexia‐Sabine; Noda, Antonio Sedeño; Pape, H.; Respondek, Gesine; Schäffer, Eva; Schneider, Martina; Schnitzler, Alfons; Schulz‐Schaeffer, Walter; Schwarz, Johannes; Skowronek, Cornelia; Storch, Alexander; Tadić, Vera; Vadász, Dávid; Zimmermann, Benno F.

doi:10.1016/s1474-4422(19)30141-3

Cited by 94 publications

(79 citation statements)

References 39 publications

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“…EGCG is a catechin present in green tea that redirects β-sheet rich amyloid into unstructured aSyn 15,16 . Nevertheles, clinical trials using EGCG were negative for reasons that are still not understood but, most probably, due to low bioavailability 21 .…”

Section: Introductionmentioning

confidence: 99%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili

Koenig

et al. 2020

Preprint

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Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the cooccurrence of both Lewy bodies and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation andinternalization of tau and aSyn. We found that anle138b and epigallocatechin gallate decrease aSyn aggregation, that fulvic acid attenuates aggregation of the repeat domain of tau, and that dynasore reduces tau internalization.Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili

Koenig

et al. 2020

Preprint

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“…MSA is a rare neurodegenerative disease where aggregation of -synuclein in oligodendrocytes and neurons has been found. The above indicated treatment did not modify disease progression in MSA and hepatotoxicity was reported in a few cases [185].…”

Section: Neurodegenerationmentioning

confidence: 85%

“…Decrease in neuro-inflammation and in liquoral levels of A40 and increase in dentate-gyrus-related cognitive functions and hippocampal memory [179,180] EGCG MSA (clinical trial) No effects [185] Abbreviations: A, Amyloid , AD, Alzheimer's disease, EGCG, epigallocatechin gallate, GSSE, grape seed and skin extract, 6-OHDA, 6-Hydroxydopamamine, IBD, inflammatory bowel disease, LPS, lipopolysaccharide, MSA, multiple system atrophy, NF-B, nuclear factor kappa-light-chain-enhancer of activated B cells, PD, Parkinson's disease, RES, resveratrol, ROS, reactive oxygen species, STAT, signal transducer and activator of transcription, TLR, Toll-like receptor.…”

Section: Neurodegenerationmentioning

confidence: 99%

Recent Advances on the Anti-inflammatory and Anti-oxidant properties of Red Grape Polyphenols: In Vitro and in Vivo Studies

Magrone¹,

Magrone²,

Russo³

et al. 2019

Preprint

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In this review, special emphasis will be placed on red grape polyphenols for their anti-oxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of pro-inflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Furthermore, the effects of red grape polyphenols will be analyzed in obesity, as a low grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great anti-oxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites and interaction with microbiota, deserve deeper studies.

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“…However, a large double-blind trial showed that rifampicin does not slow or halt progression of MSA [137]. On the other hand, a phase III randomized double blind trial on MSA patients (NCT02008721 and 2012-000928-18) assessed the effects of epigallocatechin-gallate (EGCG), a polyphenol found in green tea which reduced aggregation and toxicity of αsyn oligomers [138,139], unfortunately showing that EGCG treatment does not modify disease progression [140]. Whether the above mentioned small molecules specifically targeting α-syn oligomerization will be more potent than rifampicin and EGCG to induce disease modification in a clinical setting remains to be determined.…”

Section: α-Syn Aggregation Inhibitorsmentioning

confidence: 99%

MSA: From basic mechanisms to experimental therapeutics

Heras‐Garvin

Stefanova

2020

Parkinsonism & Related Disorders

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Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.

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Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial

Cited by 94 publications

References 39 publications

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Recent Advances on the Anti-inflammatory and Anti-oxidant properties of Red Grape Polyphenols: In Vitro and in Vivo Studies

MSA: From basic mechanisms to experimental therapeutics

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