Significant increase in
iron occurs in the substantia nigra pars compacta of Parkinsonian subjects, and in
6-hydroxydopamine (6-OHDA) treated rats and monkeys. This increase in
iron has been attributed to its release from
ferritin and is associated with the generation of
reactive oxygen species and the onset of oxidative stress-induced neurodegeneration. Several
iron chelators with hydroxyquinoline backbone were synthesized and their ability to inhibit basal as well as
iron-induced mitochondrial lipid peroxidation was examined. The neuroprotective potential of the brain permeable
iron chelator, VK-28 (5-[4-(2-hydroxyethyl)
piperazine-1-ylmethyl]-
quinoline-8-ol), injected either intraventricularly (ICV) or intraperitoneally (IP), to
6-OHDA lesioned rats was investigated. VK-28 inhibited both basal and Fe/ascorbate induced mitochondrial membrane lipid peroxidation, with an IC(50) (12.7 microM) value comparable to that of the prototype
iron chelator,
desferal, which does not cross the blood brain barrier. At an ICV pretreatment dose as low as 1 microg, VK-28 was able to completely protect against ICV
6-OHDA (250 microg) induced striatal dopaminergic lesion, as measured by
dopamine (DA), dihydroxyphenylacetic
acid (
DOPAC) and homovanilic
acid (HVA) levels. IP injection of rats with VK-28 (1 and 5 mg/kg) daily for 10 and 7 days, respectively, demonstrated significant neuroprotection against ICV
6-OHDA at the higher dose, with 68% protection against loss of
dopamine at 5mg/kg dosage of VK-28. The present study is the first to show neuroprotection with a brain permeable
iron chelator. The latter can have implications for the treatment of
Parkinson's disease and other
neurodegenerative diseases (
Alzheimer's disease,
Friedreich ataxia,
aceruloplasminemia,
Hallervorden Spatz syndrome) where abnormal
iron accumulation in the brain is thought to be associated with the degenerative processes.