Therapeutic targets and potential of the novel brain‐ permeable multifunctional iron chelator–monoamine oxidase inhibitor drug, M‐30, for the treatment of Alzheimer's disease1

Avramovich‐Tirosh, Yael; Amit, Tamar; Bar‐Am, Orit; Zheng, Hailin; Fridkin, Mati; Youdim, Moussa B. H.

doi:10.1111/j.1471-4159.2006.04258.x

Cited by 130Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesNeurological Disorders and Treatments

Therapeutic targets and potential of the novel brain‐ permeable multifunctional iron chelator–monoamine oxidase inhibitor drug, M‐30, for the treatment of Alzheimer's disease1

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Avramovich‐Tirosh, Yael, Amit, Tamar, Bar‐Am, Orit, Zheng, Hailin, Fridkin, Mati, Youdim, Moussa B. H.·2007·Journal of Neurochemistry

DOI 10.1111/j.1471-4159.2006.04258.x

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Abstract

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple CNS targets. We have synthesized a multifunctional non‐toxic, brain permeable iron chelator drug, M‐30, possessing propargyl monoamine oxidase (MAO) inhibitory neuroprotective and iron‐chelating moieties, from our prototype iron chelator VK‐28. In the present study M‐30 was shown to possess a wide range of pharmacological activities, including pro‐survival neurorescue effects, induction of neuronal differentiation and regulation of amyloid precursor protein (APP) and β‐amyloid (Aβ) levels. M‐30 was found to decrease apoptosis of SH‐SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via reduction of the pro‐apoptotic proteins Bad and Bax, and inhibition of the apoptosis‐associated phosphorylated H2A.X protein (Ser 139) and caspase 3 activation. In addition, M‐30 induced the outgrowth of neurites, triggered cell cycle arrest in G 0/G 1 phase and enhanced the expression of growth associated protein‐43. Furthermore, M‐30 markedly reduced the levels of cellular APP and β‐C‐terminal fragment (β‐CTF) and the levels of the amyloidogenic Aβ peptide in the medium of SH‐SY5Y cells and Chinese hamster ovary cells stably transfected with the APP ‘Swedish’ mutation. Levels of the non‐amyloidogenic soluble APPα and α‐CTF in the medium and cell lysate respectively were coordinately increased. These properties, together with its brain selective MAO inhibitory and propargylamine‐ dependent neuroprotective effects, suggest that M‐30 might serve as an ideal drug for neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, in which oxidative stress and iron dysregulation have been implicated.

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Multifunctional 8-hydroxyquinoline derivatives developed by Youdim and colleagues are effective bidentate iron chelators and show considerable promise in treatment of a variety of neurodegenerative diseases.
“To this end, Youdim and colleagues in particular have developed a series of multifunctional 8-hydroxyquinoline [1740] derivatives that are effective bidentate iron chelators and that seem to show considerable promise in the treatment of a variety of neurodegenerative diseases [1037,1727-1729,1780-1784]”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [1784]

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Research works printed but not linked: 5

Y. Avramovich-Tirosh et al. Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2007) 100, 490-502
Ó 2006 The Authors 14714159, 2007, 2, · DOI
Ó 2006 The Authors Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2007) 100, 490-502 14714159, 2007, 2, · DOI
Y. Avramovich-Tirosh et al. Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2007) 100, 490-502
Ó 2006 The Authors 14714159, 2007, 2, · DOI

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Authors: Avramovich‐Tirosh, Y., Amit, T., Bar‐Am, O., Zheng, H., Fridkin, M., & Youdim, M. B. H.
Affiliations: Technion – Israel Institute of Technology (IL)
Weizmann Institute of Science (IL)
ORCID: Zheng, Hailin
Youdim, Moussa B. H.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2006-10-05
Volume: 100
Issue: 2
Pages: 490-502
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1111/j.1471-4159.2006.04258.x
OpenAlex: W2082238500
Cited by: 130
References: 79
Citations by year: 2025: 2 · 2024: 2 · 2023: 1 · 2022: 7 · 2021: 9 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 7 · 2015: 10 · 2014: 9 · 2013: 8 · 2012: 13
FWCI: 5.52
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
Keywords: iron chelators, monoamine oxidase inhibitors, propargylamines, Alzheimer's disease, neuroprotection, amyloid-beta, amyloid precursor protein, neuronal differentiation, apoptosis, Bad, Bax, caspase-3, H2AX phosphorylation, neurite outgrowth, growth-associated protein 43, oxidative stress, iron dysregulation, Parkinson's disease, brain permeability
MeSH terms: Analysis of Variance, Animals, Cell Cycle, Cell Differentiation, Cell Line, Dose-Response Relationship, Drug, Flow Cytometry, Humans, Hydroxyquinolines, Iron Chelating Agents, Monoamine Oxidase Inhibitors, Neuritis, Neuroblastoma, Neurons, Amyloid beta-Protein Precursor, Apoptosis, Proto-Oncogene Proteins c-bcl-2, GAP-43 Protein, In Situ Nick-End Labeling, Immunoprecipitation, bcl-Associated Death Protein, Rats, Caspase 3

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Therapeutic targets and potential of the novel brain‐ permeable multifunctional iron chelator–monoamine oxidase inhibitor drug, M‐30, for the treatment of Alzheimer's disease1

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