| ironjustice@aol.com 2005-07-28, 8:57 am |
| J Neurochem. 2005 Jul 25; [Epub ahead of print] Links
Novel multifunctional neuroprotective iron chelator-monoamine oxidase
inhibitor drugs for neurodegenerative diseases: in vitro studies on
antioxidant activity, prevention of lipid peroxide formation and
monoamine oxidase inhibition.
Zheng H, Gal S, Weiner LM, Bar-Am O, Warshawsky A, Fridkin M, Youdim
MB.
Department of Organic Chemistry and Neurobiology, The Weizmann
Institute of Science, Rehovot, Israel.
Abstract Iron-dependent oxidative stress, elevated levels of iron and
of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in
the brain may be major pathogenic factors in Parkinson's disease,
Alzheimer's disease and related neurodegenerative diseases.
Accordingly, iron chelators, antioxidants and MAO-B inhibitors have
shown efficacy in a variety of cellular and animal models of CNS
injury. In searching for novel antioxidant iron chelators with
potential MAO-B inhibitory activity, a series of new iron chelators has
been designed, synthesized and investigated. In this study, the novel
chelators were further examined for their activity as antioxidants,
MAO-B inhibitors and neuroprotective agents in vitro. Three of the
selected chelators (M30, HLA20 and M32) were the most effective in
inhibiting iron-dependent lipid peroxidation in rat brain homogenates
with IC(50) values (12-16 microm), which is comparable with that of
desferal, a prototype iron chelator that is not has orally active.
Their antioxidant activities were further confirmed using electron
paramagnetic resonance spectroscopy. In PC12 cell culture, the three
novel chelators at 0.1 microm were able to attenuate cell death induced
by serum deprivation and by 6-hydroxydopamine. M30 possessing
propargyl, the MAO inhibitory moiety of the anti-Parkinson drug
rasagiline, displayed greater neuroprotective potency than that of
rasagiline. In addition, in vitro, M30 was a highly potent
non-selective MAO-A and MAO-B inhibitor (IC(50) < 0.1 microm). However,
HLA20 was more selective for MAO-B but had poor MAO inhibition, with an
IC(50) value of 64.2 microm. The data suggest that M30 and HLA20 might
serve as leads in developing drugs with multifunctional activities for
the treatment of various neurodegenerative disorders.
PMID: 16045440 [PubMed - as supplied by publisher]
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