Abstract
Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimers amyloid precursor protein and its toxic amyloidogenic derivative, Aβ. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1α signaling pathway, thus promoting HIF-1α mRNA and protein expression levels, as well as increasing transcription of HIF-1α-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growthassociated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimers disease (AD), western blotting analysis of glycogen synthase kinase- 3β (GSK-3β) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3β (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Aβ25-35 toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinsons disease and AD in which oxidative stress and iron-mediated toxicity are involved.
Keywords: Alzheimer's disease, neuroprotection, iron chelation, amyloidogenic Aβ peptide, hypoxia-inducible factor -1α
Current Alzheimer Research
Title: Up-Regulation of Hypoxia-Inducible Factor (HIF)-1α and HIF-Target Genes in Cortical Neurons by the Novel Multifunctional Iron Chelator Anti-Alzheimer Drug, M30
Volume: 7 Issue: 4
Author(s): Y. Avramovich-Tirosh, O. Bar-Am, T. Amit, M.B.H. Youdim and O. Weinreb
Affiliation:
Keywords: Alzheimer's disease, neuroprotection, iron chelation, amyloidogenic Aβ peptide, hypoxia-inducible factor -1α
Abstract: Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimers amyloid precursor protein and its toxic amyloidogenic derivative, Aβ. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1α signaling pathway, thus promoting HIF-1α mRNA and protein expression levels, as well as increasing transcription of HIF-1α-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growthassociated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimers disease (AD), western blotting analysis of glycogen synthase kinase- 3β (GSK-3β) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3β (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Aβ25-35 toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinsons disease and AD in which oxidative stress and iron-mediated toxicity are involved.
Export Options
About this article
Cite this article as:
Avramovich-Tirosh Y., Bar-Am O., Amit T., Youdim M.B.H. and Weinreb O., Up-Regulation of Hypoxia-Inducible Factor (HIF)-1α and HIF-Target Genes in Cortical Neurons by the Novel Multifunctional Iron Chelator Anti-Alzheimer Drug, M30, Current Alzheimer Research 2010; 7 (4) . https://dx.doi.org/10.2174/156720510791162403
DOI https://dx.doi.org/10.2174/156720510791162403 |
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
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
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
Phytochemicals Resveratrol and Sulforaphane as Potential Agents for Enhancing the Anti-Tumor Activities of Conventional Cancer Therapies
Current Pharmaceutical Biotechnology New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors
Recent Patents on CNS Drug Discovery (Discontinued) Highly Organized Nanostructures for Brain Drug Delivery - New Hope or Just a Fad?
CNS & Neurological Disorders - Drug Targets Current Evaluation of the Millennium Phytomedicine- Ginseng (II): Collected Chemical Entities, Modern Pharmacology, and Clinical Applications Emanated from Traditional Chinese Medicine
Current Medicinal Chemistry CXCR4 and Glioblastoma
Anti-Cancer Agents in Medicinal Chemistry Clinical Pharmacogenetics in Oncology: the Paradigm of Molecular Targeted Therapies
Current Pharmaceutical Design Development and Clinical Application of Peptide-Based Radiopharmaceuticals
Current Pharmaceutical Design Patents in Cancer Stem Cells
Recent Patents on Biomarkers The Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP): A New Rodent Model to Test Palliative and Neuroprotective Agents for Parkinsons disease
Current Pharmaceutical Design Natural Compounds with Proteasome Inhibitory Activity for Cancer Prevention and Treatment
Current Protein & Peptide Science Oligonucleotides and G-quadruplex Stabilizers: Targeting Telomeres and Telomerase in Cancer Therapy
Current Pharmaceutical Design Radiolabeled Oligonucleotides for Antisense Imaging
Current Organic Synthesis Functionalized Silver Nanoparticles for Sensing, Molecular Imaging and Therapeutic Applications
Current Nanomedicine Morpho-Functional Features of In-Vitro Cell Death Induced by Physical Agents
Current Pharmaceutical Design Molecular Basis for the Neuroprotective Properties of FKBP-Binding Immunophilin Ligands
Current Medicinal Chemistry - Central Nervous System Agents Impaired Quality Control of Mitochondria Underlying the Pathogenesis of Alzheimer's Disease
Current Drug Targets Estrogen Receptor Signaling: Impact on Cell Functions
Current Signal Transduction Therapy Angiotensin II, Cell Proliferation and Angiogenesis Regulator: Biologic and Therapeutic Implications in Cancer
Current Vascular Pharmacology Click Chemistry, A Potent Tool in Medicinal Sciences
Current Medicinal Chemistry Novobiocin and Additional Inhibitors of the Hsp90 C-Terminal Nucleotide- binding Pocket
Current Medicinal Chemistry