Abstract
Iron is an essential element in the metabolism of all cells. Elevated levels of the metal have been found in the brains of patients of numerous neurodegenerative disorders, including Parkinson's disease (PD). The pathogenesis of PD is largely unknown, although it is thought through studies with experimental models that oxidative stress and dysfunction of brain iron homeostasis, usually a tightly regulated process, play significant roles in the death of dopaminergic neurons. Accumulation of iron is present at affected neurons and associated microglia in the substantia nigra of PD patients. This additional free-iron has the capacity to generate reactive oxygen species, promote the aggregation of α-synuclein protein, and exacerbate or even cause neurodegeneration. There are various treatments aimed at reversing this pathologic increase in iron content, comprising both synthetic and natural iron chelators. These include established drugs, which have been used to treat other disorders related to iron accumulation. This paper will discuss how iron dysregulation occurs and the link between increased iron and oxidative stress in PD, including the mechanism by which these processes lead to cell death, before assessing the current pharmacotherapies aimed at restoring normal iron redox and new chelation strategies undergoing research.
Highlights
Parkinson’s disease is a chronic, progressive disorder and the second most common neurodegenerative disease after Alzheimer’s disease, with an overall prevalence in the general population of 0.3% [1]
Iron may constitute a link between the pathogenic events of oxidative damage and protein aggregation, with iron accumulating in Lewy bodies in Parkinson’s disease (PD) [57] and promoting alpha-synuclein aggregation [58], an event reversed by the administration of an iron chelator [59]
The correlation between iron accumulation in the brain and PD has logically led to the theory that chelators of iron could help slow the development of the disease by mopping up the unbound, free radical-enhancing iron in the brain
Summary
Parkinson’s disease is a chronic, progressive disorder and the second most common neurodegenerative disease after Alzheimer’s disease, with an overall prevalence in the general population of 0.3% [1]. Infusion of ferric iron into the SNpc can be used to create a model of dose-related, progressive parkinsonism including a reduction in dopaminergic activity [9] This can be attenuated by treatment with the lazaroid U-74389G [10], showing that iron may play a prominent causative role in the death of neurons by oxidative stress and lipid peroxidation. Loss of melanised neurons is correlated with an abundance of nonheme iron (Fe3+) and a significant increase in redox activity, which is most pronounced in patients with the greatest loss of neuromelanised cells [17] This change in redox state can contribute to oxidative stress and induce further cell death. This paper will summarise briefly the factors contributing to a dysregulation of iron in parkinsonian patients and its role in the disease pathology before discussing the methods aimed at restoring iron homeostasis
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