Abstract
Accumulation of iron at sites where neurons degenerate in Parkinsons disease (PD) and Alzheimers disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine- 1- ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.X and inhibition of the cleavage and activation of caspase-3. M-30 and EGCG also promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both compounds significantly reduced the levels of cellular holo-amyloid precursor protein (APP) in SH-SY5Y cells. The ability of theses novel iron chelators and EGCG to regulate APP are in line with the presence of an iron-responsive element (IRE) in the 5-untranslated region (5UTR) of APP. Also, EGCG reduced the levels of toxic amyloid-beta peptides in CHO cells over-expressing the APP “Swedish” mutation. The diverse molecular mechanisms and cell signaling pathways participating in the neuroprotective/neurorescue and APP regulation/processing actions of M-30 and EGCG, make these multifunctional compounds potential neuroprotective drugs for the treatment of neurodegenerative diseases, such as PD, AD, Huntingtons disease and amyotrophic lateral sclerosis.
Keywords: Alzheimer's disease, Parkinson's disease, iron, monoamine oxidase, brain permeable iron chelators, neuroprotection, neurorescue, APP, Aβ- peptide, iron regulatory protein
Current Alzheimer Research
Title: Neurorescue Activity, APP Regulation and Amyloid-β Peptide Reduction by Novel Multi-Functional Brain Permeable Iron- Chelating- Antioxidants,M-30 and Green Tea Polyphenol, EGCG
Volume: 4 Issue: 4
Author(s): Yael Avramovich-Tirosh, Lydia Reznichenko, Tamar Amit, Hailin Zheng, Mati Fridkin, Orly Weinreb, Silvia Mandel and Moussa B.H. Youdim
Affiliation:
Keywords: Alzheimer's disease, Parkinson's disease, iron, monoamine oxidase, brain permeable iron chelators, neuroprotection, neurorescue, APP, Aβ- peptide, iron regulatory protein
Abstract: Accumulation of iron at sites where neurons degenerate in Parkinsons disease (PD) and Alzheimers disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine- 1- ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.X and inhibition of the cleavage and activation of caspase-3. M-30 and EGCG also promoted morphological changes, resulting in axonal growth-associated protein-43 (GAP-43) implicating neuronal differentiation. Both compounds significantly reduced the levels of cellular holo-amyloid precursor protein (APP) in SH-SY5Y cells. The ability of theses novel iron chelators and EGCG to regulate APP are in line with the presence of an iron-responsive element (IRE) in the 5-untranslated region (5UTR) of APP. Also, EGCG reduced the levels of toxic amyloid-beta peptides in CHO cells over-expressing the APP “Swedish” mutation. The diverse molecular mechanisms and cell signaling pathways participating in the neuroprotective/neurorescue and APP regulation/processing actions of M-30 and EGCG, make these multifunctional compounds potential neuroprotective drugs for the treatment of neurodegenerative diseases, such as PD, AD, Huntingtons disease and amyotrophic lateral sclerosis.
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Avramovich-Tirosh Yael, Reznichenko Lydia, Amit Tamar, Zheng Hailin, Fridkin Mati, Weinreb Orly, Mandel Silvia and Youdim B.H. Moussa, Neurorescue Activity, APP Regulation and Amyloid-β Peptide Reduction by Novel Multi-Functional Brain Permeable Iron- Chelating- Antioxidants,M-30 and Green Tea Polyphenol, EGCG, Current Alzheimer Research 2007; 4 (4) . https://dx.doi.org/10.2174/156720507781788927
DOI https://dx.doi.org/10.2174/156720507781788927 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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