The possible role of iron in the etiopathology of Parkinson's disease.
The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.
Youdim
M B
MB
Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Ben-Shachar
D
D
Riederer
P
P
D000818:Animals; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D006801:Humans; D007501:Iron / Q000502:physiology*; D015227:Lipid Peroxidation / Q000502:physiology*; D009410:Nerve Degeneration / Q000502:physiology; D010300:Parkinson Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species; D011954:Receptors, Dopamine / Q000502:physiology; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology
D017382:Reactive Oxygen Species; D011954:Receptors, Dopamine; D007501:Iron; D004298:Dopamine