3,3-EPIGALLOCATECHIN-3-GALLATE, FROM TEA EXTRACT, ATTENUATES NEURONAL CELL DEATH IN 6-HYDROXYDOPAMINE AND MPTP MODELS OF PARKINSON'S DISEASE: POSSIBLE GENE TARGETS
Youdim, M.B.H., Mandel, S., Maor, G*. and Levites, Y
Technion - Faculty of Medicine, Eve Topf and US National Parkinson's Foundation Centers for Neurodegenerative diseases, Bruce Rappaport Family Research Institute, Department of Pharmacology, *Department of Cell Biology, Haifa, Israel.
Oxidative stress is a contributing factor to the pathogenesis of aging brain and neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. It has been demonstrated that age-related decline in neuronal signal transduction is reversed by the consumption of polyphenol-rich foods, implicating dietary polyphenols as potential neuroprotective agents. Recently we have shown that tea extracts inhibit iron-induced lipid peroxidation of brain mitochondrial fraction as well as 6-hydroxydopamine-induced cell damage in neuronal cell lines and MPTP-induced dopaminergic neurons loss in vivo. In an attempt to elucidate the neuroprotective skills of major tea polyphenol, 3,3-epigallocatechine-3-gallate (EGCG) and possible gene targets for its action, human neuroblastoma SH-SY5Y cells were treated with 6-hydroxydopamine (20æM) and MPP+ (400æM). Pretreatment for 45 min with EGCG (0.1-5æM) prevented toxin-induced cell damage, as it has been shown by MTT test. For in vivo studies, the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease was employed. C57-BL mice were treated with EGCG (4-20æmols/kg/day/14 days, orally). MPTP (24 mg/kg/day, i.p.) was given for the last 5 days. 3 days after last injection, the mice were decapitated and brains were used for further investigations. Striatal Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content were determined by HPLC. MPTP caused a marked reduction in DA levels (40% of control). However, EGCG (4æmols/kg/day/14 days) conferred a significant protection against MPTP induced DA loss, as indicated by striatal dopamine and its metabolites content (80 % of control). Gene expression profile induced by EGCG was analyzed using Atlas mouse cDNA expression array. The expression of number of different genes involved in signal transduction pathways leading to neuronal survival, such as c-jun, CREBP1, MAP3K, MEKK1/2, STAT1, IGF1R was up regulated. This study is the first to demonstrate neuroprotective activities of EGCG as well as a detailed profile of simultaneous gene changes in brain as a result of EGCG consumption. However, our recent cell culture studies with EGCG, employing human neuroblastoma cell line, SY-SY5Y have shown that neuroprotection and neuroprotective gene expression are concentration dependent. While at low concentrations (1mM) EGCG is antioxidant and neuroprotective, at higher concentrations (50mM) it is pro-oxidant and it induces apoptosis and expression of apoptotic genes.
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