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

Abstract

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.

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

“…2B), CQ administration alone and in the presence of MPTP elicited stabilization of cytosolic HIF-1␣ (Fig. 6B) suggesting that activation of the HIF pathway by CQ could in part underlie the protection against DAergic cell loss observed in various studies utilizing iron chelation therapy in MPTP PD models (13,32).…”

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…One of the well-recognized pathways responsible for generation of oxidative radicals is mitochondrial toxicity induced by accumulation of MPP + in the inner mitochondrial membrane, and the subsequent disruption of complex I in the electron transport chain (Cassarino et al, 1999;Fiskum et al, 2003;Kalivendi et al, 2003). Studies have also shown auto-oxidation of the neurotransmitter dopamine (Obata, 2002;Sidhu et al, 2004) or the interaction of MPP + with iron stores within the pigmented substantia nigra cells as possible sources of oxidative stress (Andersen, 2004;Mandel et al, 2004;Youdim et al, 2004;Mancuso et al, 2007).…”

Role of tea catechins in prevention of aging and age-related disorders

“…It has been reported that oxidative stress is involved as one of the causes in neurodegenerative disorders like AD and PKD (Gotz et al, 1990;Riederer et al, 1989;Perry et al, 2002) and age associated behaviour deficits (Shukitt-Hale, 1999). Apart from oxidative stress, inflammatory changes and iron accumulation (Gerlach et al, 2003;Youdim et al, 2004) have been suggested and reported to be involved in neurodegenerative diseases. Iron accumulation occurs in specific areas of the brain where degeneration occurs, in both PKD and AD (Riederer et al, 1989).…”