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Novel multifunctional neuroprotective iron chelator‐monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP‐induced striatal dopamine depletion
Author(s) -
Gal Shunit,
Zheng Hailin,
Fridkin Mati,
Youdim Moussa B. H.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03341.x
Subject(s) - monoamine oxidase , mptp , dopamine , homovanillic acid , pharmacology , chemistry , neuroprotection , monoamine oxidase b , monoamine neurotransmitter , 3,4 dihydroxyphenylacetic acid , neurotoxin , striatum , biochemistry , endocrinology , serotonin , dopaminergic , biology , enzyme , receptor
Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK‐28, possessing the monoamine oxidase (MAO) and neuroprotective N ‐propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO‐A and ‐B inhibitor in vitro (IC 50 , MAO‐A, 0.037 ± 0.02; MAO‐B, 0.057 ± 0.01). Acute (1–5 mg/kg) and chronic [5–10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days] in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO‐A and ‐B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N‐desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5‐HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5‐HIAA (5‐hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP ( N ‐methy‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5‐HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO‐A and ‐B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO‐B inhibitors, for which it is being developed, as MAO‐B inhibitors do not alter brain dopamine.