Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease.
Studies on postmortem brains from Parkinson's patients reveal elevated iron in the substantia nigra (SN). Selective cell death in this brain region is associated with oxidative stress, which may be exacerbated by the presence of excess iron. Whether iron plays a causative role in cell death, however, is controversial. Here, we explore the effects of iron chelation via either transgenic expression of the iron binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol (CQ) on susceptibility to the Parkinson's-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP). Reduction in reactive iron by either genetic or pharmacological means was found to be well tolerated in animals in our studies and to result in protection against the toxin, suggesting that iron chelation may be an effective therapy for prevention and treatment of the disease.
Kaur
Deepinder
D
Buck Institute for Age Research, Novato, CA 94945, USA.
Yantiri
Ferda
F
Rajagopalan
Subramanian
S
Kumar
Jyothi
J
Mo
Jun Qin
JQ
Boonplueang
Rapee
R
Viswanath
Veena
V
Jacobs
Russell
R
Yang
Lichuan
L
Beal
M Flint
MF
DiMonte
Dino
D
Volitaskis
Irene
I
Ellerby
Lisa
L
Cherny
Robert A
RA
Bush
Ashley I
AI
Andersen
Julie K
JK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D007464:Clioquinol / Q000627:therapeutic use; D004298:Dopamine / Q000032:analysis; D005293:Ferritins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D006719:Homovanillic Acid / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D051381:Rats; D013378:Substantia Nigra / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D007502:Iron Chelating Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D007464:Clioquinol; D005293:Ferritins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid