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.
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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 |
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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
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