|Ph.D Student||Levites Yona|
|Subject||Molecular Events in Dopaminergic Neurodegeneration;|
Mechanism of Neuroprotective Action of Major Green
Tea Polyphenol, (-)-Epigallocatechin-3-
|Department||Department of Biotechnology||Supervisor||Professor Emeritus Moussa Youdim|
A valid current hypothesis concerning the pathogenesis of Parkinson’s disease (PD) is an on going oxidative stress (OS), as well as inflammatory processes and elevated free iron levels, which are expressed selectively in substantia nigra (SN). Indeed, it has been shown in animal models of PD that neuroprotection can be achieved with iron chelators, nitric oxide synthase inhibitors and antioxidants. Given that tea and tea polyphenols have attracted increasing interest because of their well-reported antioxidant, iron chelating and anti-inflammatory properties, we proposed them as potential candidates for treatment of neurodegenerative diseases. In order to establish possible neuroprotective properties of Green tea (GT) and (-)-epigallocatechin-3-gallate (EGCG) in vivo, the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD has been employed. GT and EGCG prevented MPTP-induced dopamine neuron loss in SN. In order to investigate the gene events involved in the neuroprotective action of EGCG, cDNA expression array was employed. MPTP caused a reduction in the expression of immediate early genes, genes involved in apoptosis, cell cycle regulators and signal transduction pathways, implicated in neuronal survival, while EGCG attenuated it. Potential cell signaling candidates involved in this neuroprotective effect were further examined. Since EGCG also increased phosphorylated PKC, we suggest that PKC isoenzymes are involved in its neuroprotective action. In addition, gene expression analysis revealed that EGCG prevented, both the 6-OHDA-induced expression of several pro-apoptotic genes, as well as the decrease in anti-apoptotic genes, suggesting that the neuroprotective mechanism of EGCG against oxidative stress-induced cell death includes modulation of cell survival/cell cycle genes. In addition, we investigated the effect of EGCG on another neurodegenerative disorder, Alzheimer’s disease (AD), since it has been suggested that the b-amyloid peptide (Ab) toxicity involves OS. EGCG significantly increased the secretion of the non-amyloidogenic, non-toxic soluble form of the amyloid precursor protein (sAPPa) via stimulation of the PKC pathway. Our findings strongly suggest that EGCG possesses neuroprotective effects against OS-induced neurotoxicity via stimulation of PKC, regulation of survival genes and processing of APP. In conclusion, our studies have indicated that EGCG, possessing variety of pharmacological actions, may be beneficial in PD and AD and may even delay the progression of these neurodegenerative diseases.