Document Detail


Ironing iron out in Parkinson's disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28.
MedLine Citation:
PMID:  15105275     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In Parkinson's disease (PD) and its neurotoxin-induced models, 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), significant accumulation of iron occurs in the substantia nigra pars compacta. The iron is thought to be in a labile pool, unbound to ferritin, and is thought to have a pivotal role to induce oxidative stress-dependent neurodegeneration of dopamine neurons via Fenton chemistry. The consequence of this is its interaction with H(2)O(2) to generate the most reactive radical oxygen species, the hydroxyl radical. This scenario is supported by studies in both human and neurotoxin-induced parkinsonism showing that disposition of H(2)O(2) is compromised via depletion of glutathione (GSH), the rate-limiting cofactor of glutathione peroxide, the major enzyme source to dispose H(2)O(2) as water in the brain. Further, radical scavengers have been shown to prevent the neurotoxic action of the above neurotoxins and depletion of GSH. However, our group was the first to demonstrate that the prototype iron chelator, desferal, is a potent neuroprotective agent in the 6-OHDA model. We have extended these studies and examined the neuroprotective effect of intracerebraventricular (ICV) pretreatment with the prototype iron chelator, desferal (1.3, 13, 134 mg), on ICV induced 6-OHDA (250 micro g) lesion of striatal dopamine neurons. Desferal alone at the doses studied did not affect striatal tyrosine hydroxylase (TH) activity or dopamine (DA) metabolism. All three pretreatment (30 min) doses of desferal prevented the fall in striatal and frontal cortex DA, dihydroxyphenylacetic acid, and homovalinic acid, as well as the left and right striatum TH activity and DA turnover resulting from 6-OHDA lesion of dopaminergic neurons. A concentration bell-shaped neuroprotective effect of desferal was observed in the striatum, with 13 micro g being the most effective. Neither desferal nor 6-OHDA affected striatal serotonin, 5-hydroxyindole acetic acid, or noradrenaline. Desferal also protected against 6-OHDA-induced deficit in locomotor activity, rearing, and exploratory behavior (sniffing) in a novel environment. Since the lowest neuroprotective dose (1.3 micro g) of desferal was 200 times less than 6-OHDA, its neuroprotective activity may not be attributed to interference with the neurotoxin activity, but rather iron chelation. These studies led us to develop novel brain-permeable iron chelators, the VK-28 series, with iron chelating and neuroprotective activity similar to desferal for ironing iron out from PD and other neurodegenerative diseases, such as Alzheimer's disease, Friedreich's ataxia, and Huntington's disease.
Authors:
Moussa B H Youdim; Galia Stephenson; Dorit Ben Shachar
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  1012     ISSN:  0077-8923     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  2004 Mar 
Date Detail:
Created Date:  2004-04-23     Completed Date:  2004-05-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  306-25     Citation Subset:  IM    
Affiliation:
Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, and Department of Pharmacology, Technion-Rappaport Faculty of Medicine, Haifa, Israel. youdim@tx.technion.ac.il
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MeSH Terms
Descriptor/Qualifier:
3,4-Dihydroxyphenylacetic Acid / analysis
Analysis of Variance
Animals
Behavior, Animal / drug effects
Brain / anatomy & histology,  metabolism
Brocresine / pharmacology
Chromatography, High Pressure Liquid / methods
Deferoxamine / therapeutic use*
Disease Models, Animal
Dopamine
Dopamine Agents / pharmacology
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors / pharmacology
Exploratory Behavior / drug effects
Functional Laterality
Homovanillic Acid / analysis
Iron / metabolism*
Iron Chelating Agents / therapeutic use*
Levodopa / pharmacology
Male
Motor Activity / drug effects
Neurodegenerative Diseases* / chemically induced,  drug therapy,  metabolism
Neurotransmitter Agents / analysis
Oxidopamine*
Parkinson Disease* / drug therapy,  metabolism
Piperazines / pharmacokinetics,  therapeutic use
Quinolines / pharmacokinetics,  therapeutic use
Rats
Rats, Sprague-Dawley
Time Factors
Chemical
Reg. No./Substance:
0/Dopamine Agents; 0/Enzyme Inhibitors; 0/Iron Chelating Agents; 0/Levodopa; 0/Neurotransmitter Agents; 0/Piperazines; 0/Quinolines; 102-32-9/3,4-Dihydroxyphenylacetic Acid; 1199-18-4/Oxidopamine; 306-08-1/Homovanillic Acid; 555-65-7/Brocresine; 70-51-9/Deferoxamine; 7439-89-6/Iron

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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