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.