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.
Export Options
About this article
Cite this article as:
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 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
An Overview of Labeled Porphyrin Molecules in Medical Imaging
Recent Patents and Topics on Imaging (Discontinued) Atypical GTPases as Drug Targets
Anti-Cancer Agents in Medicinal Chemistry Therapeutic Potential of Hammerhead Ribozymes in the Treatment of Hyper-Proliferative Diseases
Current Pharmaceutical Biotechnology Organometallic Complexes: New Tools for Chemotherapy
Current Medicinal Chemistry Synthetic Lethal Interactions in Cancer Therapy
Current Cancer Drug Targets Inflammatory Mediators Hold the Key to Dendritic Cell Suppression and Tumor Progression
Current Medicinal Chemistry Development of Prodrugs for Enzyme-Mediated, Tumor-Selective Therapy
Current Medicinal Chemistry - Anti-Cancer Agents 1, 2-Benzisoxazole: A Privileged Structure with a Potential for Polypharmacology
Current Pharmaceutical Design Mitochondria: Prospective Targets for Neuroprotection in Parkinson's Disease
Current Pharmaceutical Design Engineered Peptides for Applications in Cancer-Targeted Drug Delivery and Tumor Detection
Mini-Reviews in Medicinal Chemistry Cyclin-Dependent Kinase Inhibition by Flavoalkaloids
Mini-Reviews in Medicinal Chemistry VIP in Inflammatory Bowel Disease: State of the Art
Endocrine, Metabolic & Immune Disorders - Drug Targets Immunotoxins Constructed with Ribosome-Inactivating Proteins and their Enhancers: A Lethal Cocktail with Tumor Specific Efficacy
Current Pharmaceutical Design Yeast-Derived β-Glucan in Combination with Anti-Tumor Monoclonal Antibody Therapy in Cancer
Recent Patents on Anti-Cancer Drug Discovery Plant Coumestans: Recent Advances and Future Perspectives in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Expression, Distribution and Regulation of Phosphodiesterase 5
Current Pharmaceutical Design Vicious Cycles Within the Neuropathophysiologic Mechanisms of Alzheimers Disease
Current Alzheimer Research Extracellular ATP and Neurodegeneration
Current Drug Targets - CNS & Neurological Disorders Flavonoids Protect Cerebrovascular Endothelial Cells through Nrf2 and PI3K from β-Amyloid Peptide-Induced Oxidative Damage
Current Neurovascular Research A Review on the Monoacylglycerol Lipase: At the Interface Between Fat and Endocannabinoid Signalling
Current Medicinal Chemistry