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

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 beta-amyloid (Abeta) 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 beta-C-terminal fragment (beta-CTF) and the levels of the amyloidogenic Abeta 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 APPalpha and alpha-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.

• Authors: Yael Avramovich-Tirosh, Tamar Amit, Orit Bar-Am, Hailin Zheng, Mati Fridkin, Moussa B H Youdim
• Journal: Journal of neurochemistry (J Neurochem) Vol. 100 Issue 2 Pg. 490-502 (Jan 2007) ISSN: 0022-3042 [Print] England
• PMID: 17144902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline
• Amyloid beta-Protein Precursor
• GAP-43 Protein
• Hydroxyquinolines
• Iron Chelating Agents
• Monoamine Oxidase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• bcl-Associated Death Protein
• Caspase 3

Topics

• Amyloid beta-Protein Precursor (metabolism)
• Analysis of Variance
• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Cycle (drug effects)
• Cell Differentiation (drug effects)
• Cell Line
• Dose-Response Relationship, Drug
• Flow Cytometry (methods)
• GAP-43 Protein (metabolism)
• Humans
• Hydroxyquinolines (chemistry, pharmacology)
• Immunoprecipitation (methods)
• In Situ Nick-End Labeling (methods)
• Iron Chelating Agents (chemistry, pharmacology)
• Monoamine Oxidase Inhibitors (chemistry, pharmacology)
• Neuritis (drug therapy)
• Neuroblastoma (pathology)
• Neurons (cytology, drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats
• bcl-Associated Death Protein (metabolism)