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PMID: 19609632 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30.

Neurotoxicity research ·Vol. 17 ·No. 1 ·2010-01-00 ·Pages 15-27

Gal S, Zheng H, Fridkin M, Youdim MB

Abstract

The anti-Parkinson iron chelator-monoamine oxidase inhibitor M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and ALS. In the present study we sought to examine the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue paradigm, M30 orally administered to mice for 14 days (2.5 mg/kg/day) following MPTP was shown to significantly elevate striatal dopamine levels, reduce its metabolism, and elevate tyrosine-hydroxylase protein levels (from 25.86 +/- 5.10 to 68.35 +/- 10.67% of control) and activity (from 7.52 +/- 0.98 to 16.33 +/- 2.92 pmol/mg protein/min). Importantly, M30 elevated MPTP-reduced dopaminergic (from 62.8 +/- 4.1 to 84.2 +/- 5.9% of control) and transferrin receptor (from 31.3 +/- 2.6 to 80.4 +/- 7.6% of control) cell count in the SNpc. Finally, M30 was shown to decrease mitosis, thus providing additional protection. These findings suggest that brain-permeable M30 may clearly be of clinical importance for the treatment of PD.

MeSH Terms
3,4-Dihydroxyphenylacetic Acid/metabolism Analysis of Variance Animals Brain Chemistry/drug effects Cell Division/drug effects Chromatography, High Pressure Liquid/methods Corpus Striatum/pathology Disease Models, Animal Dopamine/metabolism Dose-Response Relationship, Drug Drug Interactions Electrochemistry/methods Homovanillic Acid/metabolism Hydroxyquinolines/therapeutic use MPTP Poisoning/drug therapy,pathology Male Mice Mice, Inbred C57BL Neurons/drug effects Receptors, Transferrin/metabolism Serotonin/metabolism Substantia Nigra/pathology Time Factors Tyrosine 3-Monooxygenase/metabolism
Chemicals
5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline Hydroxyquinolines Receptors, Transferrin 3,4-Dihydroxyphenylacetic Acid Serotonin Tyrosine 3-Monooxygenase Dopamine Homovanillic Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Gal Shunit
Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine, Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Efron St, P.O. Box 9697, Haifa, 31096, Israel.
Zheng Hailin
Fridkin Mati
Youdim Moussa B H
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Article Info
Journal
Neurotoxicity research
Abbr.
Neurotox Res
ISSN
1476-3524
DOI
10.1007/s12640-009-9070-9
Published
2010-01-00
Epub
2009-00-16
Pages
15-27
Language
English
Region
United States
NLM ID
100929017
Subset
IM
External Links
PubMed source DOI: 10.1007/s12640-009-9070-9 View journal details
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