Ferrous-citrate complex and nigral degeneration: evidence for free-radical formation and lipid peroxidation.
Increased nigral iron content in the parkinsonian brain is now well documented and is implicated in the pathogenesis of this movement disorder. Free iron in the pigmented DA-containing neurons catalyze DA autoxidation and Fenton reaction to produce cytotoxic .OH, initiating lipid peroxidation and consequent cell damage. The present results clearly demonstrate that a regional increase in the levels of the "labile iron pool" can result in the degeneration of dopaminergic nigral neurons as reflected by a significant inhibition in the expression of tyrosine hydroxylase mRNA and DA depletion. Iron-complex-induced damage of dopaminergic neurons in the substantia nigra, might have resulted from a sequence of cytotoxic events including the .OH generation and lipid peroxidation as demonstrated in this study. This free-radical-induced oxidative nigral injury may be a reliable free-radical model for studying parkinsonism and may be relevant to idiopathic Parkinson's disease. This apparent nigral injury stimulated by Fe(2+)-citrate is more severe than that produced by ferric iron and its citrate complex. Moreover, these data indicate that Fe(2+)-citrate is as potent as MPP+ in causing oxidative injury to the substantia nigral neurons. However, the nigral toxicity of MPTP and its congeners are not progressive, while Fe(2+)-citrate complex may produce a progressive degeneration of the nigrostriatal neurons which is similar to the progression of ideopathic Parkinson's disease. Thus, this unique Fe(2+)-citrate complex animal model could be used for studying neuroprotective treatments for retarding or halting the progressive nigrostriatal degeneration caused by free radicals in the iron-rich basal ganglia.
Laboratory of Clinical Sciences, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1264.
K P
KP
Mohanakumar
A
A
de Bartolomeis
R M
RM
Wu
K J
KJ
Yeh
L M
LM
Sternberger
S Y
SY
Peng
D L
DL
Murphy
C C
CC
Chiueh
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D019343:Citric Acid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D005296:Ferrous Compounds; D005609:Free Radicals; D015102:3,4-Dihydroxyphenylacetic Acid; D019343:Citric Acid; D017665:Hydroxyl Radical; C016600:ferrous citrate; D004298:Dopamine