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Review
. Winter 2008;14(4):352-65.
doi: 10.1111/j.1755-5949.2008.00060.x.

Simultaneous Manipulation of Multiple Brain Targets by Green Tea Catechins: A Potential Neuroprotective Strategy for Alzheimer and Parkinson Diseases

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Free PMC article
Review

Simultaneous Manipulation of Multiple Brain Targets by Green Tea Catechins: A Potential Neuroprotective Strategy for Alzheimer and Parkinson Diseases

Silvia A Mandel et al. CNS Neurosci Ther. .
Free PMC article

Abstract

Current therapeutic approaches for Alzheimer and Parkinson disease (AD and PD, respectively) are merely symptomatic, intended for the treatment of symptoms, but offer only partial benefit, without any disease-modifying activity. Novel promising strategies suggest the use of antiinflammatory drugs, antioxidants, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid precursor protein (APP)-processing secretases, gamma and beta (that generate the amyloid-beta peptides, Abeta), anti-Abeta aggregation molecules, the interference with lipid cholesterol metabolism and naturally occurring plant flavonoids to potentially reverse the course of the diseases. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD, and PD. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. In the current article, we review the literature on the impact of the multimodal activities of green tea polyphenols and their neuroprotective effect on AD and PD.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multifunctional activities of green tea catechins. The diverse pharmacological activities of green tea polyphenols may account for their antioxidant, antiinflammatory, anticarcinogenic, and neuroprotective actions and possible benefits on diabetes and cardiovascular system.
Figure 2
Figure 2
Effect of EGCG on sAPPα release in PC12 cells. PC12 cells were preincubated for 30 min with vehicle alone, or with the general PKC inhibitor, GF109203X (upper panel) or the hydroxamic acid‐based metalloprotease inhibitor of α‐secretase, Ro31–9790 (lower panel), followed by a 2‐h exposure to EGCG or the PKC activator, phorbol 12‐myristate 13‐acetate (PMA). Proteins released into the conditioned media were collected and analyzed for sAPPα. Treatment with either EGCG or PMA resulted in an increased release of sAPPα. The observation that both inhibitors attenuated the release of sAPPα induced by EGCG or PMA, suggests the involvement of a PKC‐ and an α‐secretase‐dependent pathway in EGCG effect. Adapted from [39].
Figure 3
Figure 3
Effect of EGCG on the regulation of the iron metabolism‐related proteins APP and TfR and suppression by iron. (A and B) Human neuroblastoma SH‐SY5Y cells were incubated without or with EGCG (10 μM) or DFO (10 and 50 μM; positive control) for 2 h, and then treated with or without increasing concentrations of Fe2SO4 (10 and 50 μM) for 2 days. APP and TfR, an iron homeostasis protein negatively regulated by iron, were evaluated by Western blot analysis using 22C11 and anti‐TfR antibodies, respectively. EGCG markedly reduced holo‐APP protein levels, while addition of Fe(II) reversed the EGCG‐suppressive effect (A). The positive effect of EGCG on TfR levels was also blocked by Fe(II) (B). Iron chelation by DFO, which, by being a pure iron chelator, served as positive control, generated a similar response in both proteins. (C) The efficacy of EGCG as an iron chelator, to modulate the translation of a luciferase reporter gene driven by the APP 5′‐UTR sequences, was tested in U‐87‐MG glioma cells, cotransfected with 10 μg of DNA from pGALA plasmid (APP 5′‐UTR + APP 3′‐UTR sequences) and 5 μg of DNA from a construct that expresses GFP, to standardize for transfection efficiency. Cell plates were grown in the absence (control) or presence of increasing concentrations of EGCG (1–10 μM) for 48 h. Values represent luciferase activity normalized to GFP (mean ± SEM, from four independent experiments, each conducted in six replicates). *P < 0.01, versus untreated control. EGCG gradually suppressed APP 5′‐UTR reporter gene expression in a concentration‐dependent manner.
Figure 4
Figure 4
A schematic model illustrating the proposed mechanisms of green tea/EGCG neuroprotective/neurorescue action. This scheme summarizes suggested optional mechanisms of neuroprotective/neurodifferentiative action of EGCG: our pioneer studies have demonstrated an immediate and specific activation of PKC upon administration of EGCG, constituting one major pathway mediating its neuroprotective activity. This, in turn, may activate various survival pathways that can contribute as well to EGCG beneficial effect. One of them is related to the fast degradation of Bad in a PKC‐ and proteasomal‐dependent manner, the maintenance of mitochondrial potential and reduced expression of apoptotic genes upon oxidative stress in response to EGCG. Other PKC‐accredited beneficial effects of green tea polyphenols maybe related to activation of α‐secretase to promote generation of the nontoxic, nonamyloidogenic neurotrophic, soluble amyloid precursor protein‐alpha (sAPPα). In addition, EGCG was shown to regulate APP protein at the translational level via reduction of the labile iron pool. The net result of the latter two processes will be the reduction of Aβ fibrils formation. Additional targets of EGCG associated with its iron‐chelating effect involve the capacity of the catechin to interfere with cell cycle progression and inhibition of the iron‐dependent hypoxia‐inducible factor (HIF)‐1 prolyl‐4‐hydroxylase that regulates HIF stability, resulting in selective induction of cell survival genes including VEGF, erythropoietin, and HO‐1. Green tea catechins are also potent oxygen and nitrogen radical scavengers and inducers of endogenous antioxidant defenses. Aβ, amyloid beta‐peptide; α‐syn, alpha synuclein; HIF‐1, hypoxia‐inducible factor‐1; PKC, protein kinase C; sAPPα, soluble amyloid precursor protein‐alpha; VEGF, vascular endothelial growth factor.

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