EFFECT OF DIETARY IRON ON MOTOR BEHAVIOR AND NEURONAL DEATH IN AN EXPERIMENTAL MODEL OF PARKINSONISM
C.W. Levenson*, W. Duan, R.G. Cutler, M.P. Mattson
Laboratory of Neurosciences, National Institutes on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224.
Because of the role of iron in oxidative processes, it has been
speculated that high dietary iron may make neurons more vulnerable to
damage and exacerbate neurodegenerative disorders associated with
aging. This hypothesis is supported by the fact that high iron levels
have been implicated in the development of Parkinson's disease (PD).
Thus, this work was designed to test the impact of three levels of
dietary iron on motor behavior and the development of an experimental
model of PD. Two-month-old male C57BL/6 mice were fed diets containing
low (4 ppm), normal (48 ppm) or high (400 ppm) iron for 6 weeks prior
to the administration of MPTP, a mitochondrial toxin that causes the
death of nigro-striatal dopaminergic neurons and induces PD-like
symptoms. As expected, in mice fed the normal iron diet, MPTP impaired
motor behavior as determined by the rotarod test (p<0.05). The low iron
diet appeared to provide protection against the effects of MPTP on
motor behavior, as the number of falls was not different from controls. Six weeks of iron
supplementation significantly impaired motor behavior (p<0.001), and
the combination of high dietary iron and MPTP treatment proved to be
lethal. To understand the mechanisms that may be responsible for
iron-induced neuronal death, primary cultures of rat hippocampal
neurons were treated with increasing levels of iron. Iron treatment
resulted in a dose-dependent decrease in neuronal survival that had the
morphological characteristics of apoptosis, and was accompanied by
increases in the generation of mitochondrial reactive oxygen species
(ROS), and expression of the chaperone protein Hsp 70 and the
pro-apoptotic tumor suppressor protein p53. Furthermore, cholesterol
loading of cells prior to iron treatment significantly increased ROS
production and decreased cell survival suggesting that iron,
cholesterol, and its oxidative products may act synergistically to
impair neuronal survival. In conclusion, these data suggest that dietary iron may play a role in the vulnerability of neurons
to insults associated with PD and other neurodegenerative disorders.
Key words:
iron, parkinson's disease, p53
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