DISTRIBUTION OF IRON IN DIFFERENT BRAIN-REGIONS AND SUBCELLULAR COMPARTMENTS IN PARKINSONS-DISEASE
DISTRIBUTION OF IRON IN DIFFERENT BRAIN-REGIONS AND SUBCELLULAR COMPARTMENTS IN PARKINSONS-DISEASE
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DOI：
10.1002/ana.410320717
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发表时间：
1992-01-01
影响因子：
11.2
通讯作者：
YOUDIM, MBH
中科院分区：
文献类型：
--
作者：
RIEDERER, P;DIRR, A;YOUDIM, MBH
Careful attention should be given to the role of iron in brain physiology, because tissue iron deficiency and iron overload represent prevalent metabolic disorders. The essential participation of iron in brain development and maturation indicates that an abnormality of early iron metabolism could have profound, even long-term irreversible consequences [l-31. Iron deficiency as a cofactor of many heme and nonheme enzymes would alter many metabolic processes, including synthesis of protein, DNA, and RNA 14, 51. Excessive accumulation of tissue iron may lead to oxidative stress via formation of oxygen free radicals, which can be highly cytotoxic 16, 71. Such a phenomenon has now been implicated in Parkinson's disease (PD)[S}. The mechanism of neurotoxicity that leads to degeneration of nigrostriatal dopamine neurons of zona com-pacts, which in turn leads to a deficiency of dopamine in PD, remains obscure. On numerous occasions, involvement of endogenously or exogenously produced neurotoxins has been implicated in the progression of PD. Evidence, however, is lacking, even though synthetic neurotoxins such as N-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP) and 6-hydroxydopamine produce a parkinsonian syndrome in humans and animals [91. It is apparent that during normal aging of human brain there is loss of melanized nigrostriatal neurons. When approximately 80% of the neurons are lost, symptoms (eg, akinesia, tremor, rigidity) of PD appear. PD is characterized by an accelerated degeneration of pigmented (melanized) dopamine neurons in the pars compacta of the substantia nigra (SN). The neurons project to the striatum, where they regulate dopamine-dependent motor activity and synthesize, store, release, and catabolize dopamine as their neurotransmitter. The characteristic pigmentation of the SN is related to formation of neuromelanin as a result of polymerization of autooxidative products of dopamine. Dopamine can also be oxidatively metabolized by the enzyme monoamine oxidase (MAO-A and MAO-B), which is highly active in the basal ganglia.The presence of lipid and highly localized large deposits of iron in neurotransmitter-rich brain regions (such as the SN, the globus pallidus, and the caudate nucleus) makes the brain an ideal organ for oxidative stress resulting from metal-induced lipid peroxidation in the presence of hydrogen peroxide (H202)[lo]. Both oxidative deamination and autooxidation of dopamine result in generation of H202. In addition, iron activates tyrosine hydroxylase, which could increase dopamine levels El 1, 121. An inability to detoxify H202 (ie, catalase, peroxidase, glutathione peroxidase) could result in its accumulation, and its interaction with Fe2+ may promote the Fenton reaction. Iron-induced oxidative stress and lipid peroxidation can proceed optimally with either Fe2+ or Fe3+, provided mechanisms exist to facilitate the interconversion of iron between its oxidation-reduction (redox) states. Fe3+ can be converted to Fe2+ in the presence of endogenous reducing agents, such as ascorbate and glutathione.
