טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentReznichenko Lydia
SubjectNeurorescue Mechanisms of the Green Tea Polyphenol
(-)-Epigallocatechin-3-Gallate (EGCG) in Cell
Culture and Animal Models of
Neurodegeneration
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim
Full Thesis textFull thesis text - English Version


Abstract

Human epidemiological and new animal data suggest that tea drinking may help to protect the brain as we age. Ordinarily viewed as simple radical scavengers, green tea catechin polyphenols are considered at present compounds that invoke a spectrum of cellular mechanisms of action related to their neuroprotective activities.

Previous studies have shown the ability of the major green tea catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) to prevent neurotoxin- or serum deprivation induced cell death in neuronal cultures. In the present study we sought to determine possible ‘neurorescue’ properties of EGCG by causing extensive tissue damage before administration of EGCG. Rat pheochromocytoma cells were initially subjected to serum-starvation conditions before administration of EGCG. In spite of the high percentage of cell death, single or repetitive administration of EGCG significantly attenuated it and enhanced neuronal survival. The neurorescue effect of EGCG was abolished by pre-treatment with the protein kinase C (PKC) inhibitor, suggesting the involvement of the PKC pathway in neurorescue by the compound. The correlative neuritogenesis activity of EGCG may also contribute to its neurorescue effect.

Brain iron dysregulation and its association with amyloid precursor protein (APP) plaque formation are implicated in Alzheimer’s disease (AD) pathology. We thus examined the effect of EGCG, which possesses potent iron chelating activity, on the regulation of the iron-regulated proteins APP protein and transferrin receptor (TfR) in human SH-SY5Y neuroblastoma cells. Indeed, EGCG dose dependently increased TfR protein and mRNA levels, and significantly reduced APP, without altering mRNA levels, suggesting a post-transcriptional action. In support, EGCG suppressed the translation of a luciferase reporter gene fused to the APP mRNA 5’-untranslated region, encompassing the APP iron-responsive element. The finding that Fe2SO4 reversed the action of EGCG on APP and TfR proteins reinforces the likelihood that these effects are mediated through modulation of the intracellular iron pool. Furthermore, EGCG reduced toxic β-amyloid peptide generation in cell culture model of AD.

The neurorescue activity of EGCG was further confirmed in vivo, employing mice model of Parkinson’s disease (PD). A continuous 14-day administration of EGCG following dopaminergic lesion significantly attenuated the reduction in striatal dopamine (DA) content and reduced DA turnover. The beneficial effect of EGCG was potentiated by addition of our novel anti-PD drug, rasagiline, N-propargyl-1(R)-aminoindan to the treatment, restoring the dopaminergic cell number close to that of control. Clearly, combination drug therapy may have important implications for PD, AD and other neurological disorders as a disease modifying approach.