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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\u2010dependent neurodegeneration of dopamine neurons via Fenton chemistry. The consequence of this is its interaction with H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>to generate the most reactive radical oxygen species, the hydroxyl radical. This scenario is supported by studies in both human and neurotoxin\u2010induced parkinsonism showing that disposition of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>is compromised via depletion of glutathione (GSH), the rate\u2010limiting cofactor of glutathione peroxide, the major enzyme source to dispose H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>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\u2010OHDA 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\u2010OHDA (250 \u03bcg) 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\u2010OHDA lesion of dopaminergic neurons. A concentration bell\u2010shaped neuroprotective effect of desferal was observed in the striatum, with 13 \u03bcg being the most effective. Neither desferal nor 6\u2010OHDA affected striatal serotonin, 5\u2010hydroxyindole acetic acid, or noradrenaline. Desferal also protected against 6\u2010OHDA\u2010induced deficit in locomotor activity, rearing, and exploratory behavior (sniffing) in a novel environment. Since the lowest neuroprotective dose (1.3 \u03bcg) of desferal was 200 times less than 6\u2010OHDA, 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\u2010permeable iron chelators, the VK\u201028 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.<\/jats:p>","DOI":"10.1196\/annals.1306.025","type":"journal-article","created":{"date-parts":[[2004,4,23]],"date-time":"2004-04-23T03:27:51Z","timestamp":1082690871000},"page":"306-325","source":"Crossref","is-referenced-by-count":194,"title":["Ironing Iron Out in Parkinson's Disease and Other Neurodegenerative Diseases with Iron Chelators: A Lesson from 6\u2010Hydroxydopamine and Iron Chelators, Desferal and VK\u201028"],"prefix":"10.1111","volume":"1012","author":[{"given":"MOUSSA B. 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