Name: Epigallocatechin Gallate (EGCG)
Synonyms: Sunphenon EGCg
Therapy Type: Dietary Supplement (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Down's Syndrome, Multiple System Atrophy
U.S. FDA Status: Alzheimer's Disease (Phase 2/3), Down's Syndrome (Phase 2), Multiple System Atrophy (Phase 3)
Company: Taiyo International
EGCG is a polyphenolic flavonoid extracted from green tea leaves and widely considered to be the key bioactive ingredient of green tea. It has been reported to have beneficial effects ranging from anti-tumor and anti-inflammatory to neuroprotective. EGCG has been reported to affect multiple biological pathways, such as gene expression, growth factor-mediated signaling, mitogen-activated protein kinase-dependent pathways, antioxidant pathways, and ubiquitin/proteasome degradation. Specifically in neurodegeneration research, EGCG has been proposed to inhibit the formation of toxic oligomers by steering misfolded Aβ, α-synuclein, and mutant huntingtin away from folding pathways that lead to amyloidogenic β-sheet structures, either by binding the protein directly or possibly by acting on a protein chaperone (see May 2008 news story). EGCG has also been proposed to increase α-secretase cleavage of the amyloid precursor protein (Obregon et al., 2006).
EGCG's effects are consistently reported in vitro. In vivo, however, EGCG is unstable. Its bioavailability in target tissues has been questioned, and efforts to develop synthetic analogs with stronger pharmacological drug properties are underway (see Mereles & Hunstein 2011; Landis-Piwowar et al., 2013).
More than 60 trials on various EGCG extracts and formulations have been conducted or are ongoing, the majority on various types of cancer.
In Alzheimer's disease, one Phase 2/3 study conducted at Charite University in Berlin is comparing 18 months of treatment with EGCG to placebo in one group of patients who also take donepezil and another group who do not. The trial enrolls early stage patients and measures change on the ADAS-cog battery as the primary outcome. The trial started in October 2009 and is set to run through June 2014.
In 2012 and 2013, a separate Phase 2 trial conducted at the Parc de Salut Mar Hospital in Barcelona assessed the effect of 12 months of treatment with EGCG on various cognitive outcomes and plasma amyloid beta biomarkers in 100 Down's syndrome patients, age 14 to 29, to assess whether EGCG slows down the development of AD-like symptoms and biomarkers in people with Down's. Secondary outcomes include further cognitive and brain imaging tests, among others. Trial results have not been published, but see de la Torre et al., 2012).
In January 2014, a Phase 3 trial ramped up at Ludwig Maximilians Universität and Technische Universität, both in Munich, to evaluate EGCG in multiple-system atrophy. MSA is a rapidly progressing Parkinsonian disease that responds poorly to dopaminergic therapy and for which there is no effective therapy. In this trial, 86 patients with clinically possible or probable MSA will take EGCG for one year and be compared to patients on placebo on the Unified MSA Rating Scale (UMSARS-ME) and other clinical and neuroimaging outcomes
EGCG has also been evaluated in multiple sclerosis, Huntington's disease, and Fragile X, as well as in many non-neurological conditions. For all clinical trials of EGCG, see clinicaltrials.gov.
- de la Torre R, Dierssen M. Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future. Prog Brain Res. 2012;197:1-14. PubMed.
- Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart J, Zeng J, Mori T, Arendash GW, Shytle D, Town T, Tan J. ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 2006 Jun 16;281(24):16419-27. PubMed.
- Mereles D, Hunstein W. Epigallocatechin-3-gallate (EGCG) for Clinical Trials: More Pitfalls than Promises?. Int J Mol Sci. 2011;12(9):5592-603. Epub 2011 Aug 31 PubMed.
- Landis-Piwowar K, Chen D, Foldes R, Chan TH, Dou QP. Novel epigallocatechin gallate analogs as potential anticancer agents: a patent review (2009 - present). Expert Opin Ther Pat. 2013 Feb;23(2):189-202. Epub 2012 Dec 12 PubMed.
- Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, Engemann S, Pastore A, Wanker EE. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol. 2008 Jun;15(6):558-66. PubMed.
- Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. PubMed.
- Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5. PubMed.
- Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S. Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem. 2001 Sep;78(5):1073-82. PubMed.
- Caruana M, Högen T, Levin J, Hillmer A, Giese A, Vassallo N. Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds. FEBS Lett. 2011 Apr 20;585(8):1113-20. Epub 2011 Mar 31 PubMed.
- Mandel SA, Avramovich-Tirosh Y, Reznichenko L, Zheng H, Weinreb O, Amit T, Youdim MB. Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals. 2005;14(1-2):46-60. PubMed.