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| J Neural Transm. 2004 Oct-Nov;111(10-11):1455-71. Epub 2004 Apr 20. Links
Novel bifunctional drugs targeting monoamine oxidase inhibition and iron
chelation as an approach to neuroprotection in Parkinson's disease and other
neurodegenerative diseases.
Youdim MB, Fridkin M, Zheng H.
Eve Topf and National Parkinson Foundation Centers of Excellence for
Neurodegenerative Diseases Research, and Department of Pharmacology,
Technion-Rapapport Faculty of Medicine, Haifa, Israel.
Iron has been shown to accumulates at site where neurons degenerate in
neurodegenerative diseases of Parkinson's disease, Alzheimer's disease,
Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron
is thought to participate or initiate oxidative stress via generation of
reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are
neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic
neurotoxicity in rats and mice. However, their action on monoamine oxidase
(MAO) A and B have not been determined previously since MAO-B inhibitors have
been shown to be neuroprotective in cellular and animal models of Parkinson's
disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl,
U74500A and U74600F showed a preference for inhibition of rat brain
mitochondrial MAO-A over MAO-B. Their IC(50) ranged from 10(-3) M to 10(-6) M,
with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and
potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron
chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A
and B by 21-amino steroids (Lazaroids) were time dependent and irreversible.
Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were
fully reversible by enzyme dilution experiments. Both Fe(2+) and Fe(3+) reverse
the MAO-A and B inhibition induced by the latter chelators, but not those
initiated by 21-amino steroids. The data infer that either the inhibition of
MAO by 21-amino steroids is either the resultant of their conversion to an
irreversible covalently bound ligand or that the iron chelation moiety and MAO
inhibitory activity in these compounds are not mutually shared. The results
suggest that bifunctional brain penetrable drugs with iron chelating property
and MAO inhibitory activity in could be the most feasible approach for
neuroprotection in neurodegenerative diseases. Such drug would prevent
participation of elevated iron in oxidative stress and formation of reactive
hydroxyl radical, via its interaction with H(2)O2 (Fenton chemistry), generated
as a consequence MAO and other oxidative enzyme reactions to generative
cytotoxic reactive hydroxyl radical. We have now developed several of these
compounds with neuroprotective, MAO inhibitory and iron chelating properties
from our prototype iron chelators, VK-28 possessing propargylamine moiety of
our anti-parkinson drug, rasagiline.
PMID: 15480846 [PubMed - in process]
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