| ironjustice@aol.com 2006-06-04, 9:21 am |
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<<snip>>
The copper chelator, D-penicillamine, does not attenuate MPTP induced
dopamine depletion <<snip>>
<<snip>>
treatment with M30 results in increased levels of dopamine (DA)
<<snip>>
<<snip>>
iron chelating potency similar to desferal
<<snip>>
J Neurochem. 2005 Oct;95(1):79-88. Related Articles, Links
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.
Gal S, Zheng H, Fridkin M, Youdim MB.
Eve Topf and US National Parkinson Foundation Centers of Excellence for
Neurodegenerative Diseases, Technion-Rappaport Family Faculty of
Medicine and Department of Pharmacology, Haifa, Israel.
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 (IC50, 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.
PMID: 16181414 [PubMed - indexed for MEDLINE]
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J Neural Transm. 2006 Jun 1; [Epub ahead of print] Related Articles,
Links
The copper chelator, D-penicillamine, does not attenuate MPTP induced
dopamine depletion in mice.
Youdim MB, Grunblatt E, Mandel S.
Eve Topf and US National Parkinson Foundation, Centers of Excellence
For Neurodegenerative Diseases Research, Technion-Rappaport Family
Faculty of Medicine, Haifa, Israel, Youdim@tx.technion.ac.il.
In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and
6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson's
disease iron accumulates in substantia nigra pars compacta which has
been suggested to participate in oxidative stress induced
neurodegeneration. Pretreatment with iron chelators desferal,
clioquinol, VK-28 and M30 are neuroprotective in both models. To
determine the specificity of chelation neuroprotective activity we have
examined the effect of D-penicillamine, a relatively specific copper
chelator, in the mice model of MPTP-induced dopamine depletion. Our
studies show that D-penicillamine, employed for removal of copper in
Wilson disease is relatively weak in preventing dopaminergic
neurotoxicity induced by MPTP, as compared to iron chelators previously
studied. The results indicate that for prevention of MPTP-induced
dopamine depletion and dopamine neurodegeneration, iron rather than
copper chelation may be more effective and specific.
PMID: 16736232 [PubMed - as supplied by publisher]
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