GREEN TEA POLYPHENOL (-)-EPIGALLOCATECHIN-3-GALLATE; A NOVEL NEUROPROTECTIVE AND NEURORESCUE AGENT FOR TREATMENT OF AGEING BRAIN
Silvia Mandel*, Tamar Amit, Lydia Reznichenko, Limor Tal, Orly Weinreb and Moussa B. H. Youdim
Eve Topf and US National Parkinson's Foundation Centers of Excellence for Neurodegenerative Diseases, Bruce Rappaport Family Research Institute and Departments of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
We have recently reported that both green tea extract, as well and its main polyphenol constituent, (-)-epigallocatechin-3-gallate (EGCG) possess potent neuroprotective activity in cell culture and in mice MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease, part of which may be explained by their radical scavenging-iron chelating actions. However, the cell signaling mechanism implicated in this action is unknown. We have extended our in vivo studies to neuronal cell culture employing the neurotoxins, 6-hydroxydopamine (6-OHDA,50uM), 1-methyl-4-phenylpyridinium (MPP+, 400uM) and amyloid-beta peptides (Abeta1-25, 1-40, 1-42 10uM) to induce cell damage. Pretreatment with EGCG (0.1-10µM) markedly attenuated human neuroblastoma (NB) SH-SY5Y and rat PC12 cell death, induced by 24 h exposure to the toxins or by serum withdrawal, as assessed by nucleosome formation and mitochondrial function analysis. EGCG was able not only to prevent, but also to rescue the neurons when applied after Abeta-induced cell damage or 4 days after serum deprivation. Potential cell signaling candidates involve in this neuroprotective effect were further examined. EGCG restored the reduced protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) activities, caused by 6-OHDA toxicity. Furthermore, EGCG (0.1-10µM) considerably increased (~8-fold) the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPbeta) into the conditioned media in both cell lines. Thus, EGCG may affect APP metabolism by shifting the balance of ?-secretase-mediated APP processing towards a presumably non-pathogenic pathway. The positive effect of EGCG on cell survival and sAPP secretion, was abolished by pretreatment with PKC inhibitor GF109203X (1µM), indicating the involvement of PKC in the stimulated effect. In addition, customized cDNA microarray expression analysis and confirmatory real-time PCR and protein determination revealed that EGCG decreased the expression of pro-apoptotic Bcl-2-family members Bax, caspase-1, cyclin dependent kinase (cdk) inhibitor p21 (Waf1), mdm2, growth arrest and DNA-damage-inducible protein GADD45 (gadd45 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNAs. We also demonstrated a concentration-dependent correlation between EGCG structurally-related antioxidant compounds and modulation of cell survival/ cell death-related gene pathways. Given the potent antioxidant, neurorescue and enhancing sAPP release properties of EGCG, we suggest that this polyphenol may significantly and beneficially delay the progression of neurodegenerative disorders such as Alzheimer's, Parkinson's and Lewy body diseases.
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