Role of dietary iron restriction in a mouse model of Parkinson's disease.
There is a growing body of evidence suggesting that iron chelation may be a useful therapy in the treatment of Parkinson's Disease (PD). Experiments were designed to test the impact of dietary iron availability on the pathogenic process and functional outcome in a mouse model of PD. Mice were fed diets containing low (4 ppm) or adequate (48 ppm) amounts of iron for 6 weeks before the administration of MPTP, a mitochondrial toxin that damages nigrostriatal dopaminergic neurons and induces Parkinson-like symptoms. Low dietary iron increased serum total iron binding capacity (P < 0.001). Consistent with neuronal protection, iron restriction increased sphingomyelin C16:0 and decreased ceramide C16:0. However, there was a 35% decrease in striatal dopamine (DA) in iron-restricted mice. Motor behavior was also impaired in these animals. In vitro studies suggested that severe iron restriction could lead to p53-mediated neuronal apoptosis. Administration of MPTP reduced striatal DA (P < 0.01) and impaired motor behavior in iron-adequate mice. However, in iron-restricted mice, striatal dopamine levels and motor behavior were unchanged compared to saline-treated mice. Thus, while reduced iron may provide protection against PD-inducing insults such as MPTP, the role of iron in the synthesis of DA and neuronal survival should be considered, particularly in the development of iron-chelating agents to be used chronically in the clinical setting.
Levenson
Cathy W
CW
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. levenson@neuro.fsu.edu
Cutler
Roy G
RG
Ladenheim
Bruce
B
Cadet
Jean L
JL
Hare
Joan
J
Mattson
Mark P
MP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D007150:Immunohistochemistry; D019266:Iron, Dietary / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D013109:Sphingomyelins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
D002518:Ceramides; D019266:Iron, Dietary; D013109:Sphingomyelins; D016159:Tumor Suppressor Protein p53; D004298:Dopamine