The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson's disease.

Although the aetiology of Parkinson's disease (PD) and related neurodegenerative disorders is still unknown, recent evidence from human and experimental animal models suggests that a misregulation of iron metabolism, iron-induced oxidative stress and free radical formation are major pathogenic factors. These factors trigger a cascade of deleterious events leading to neuronal death and the ensuing biochemical disturbances of clinical relevance. A review of the available data in PD provides the following evidence in support of this hypothesis: (i) an increase of iron in the brain, which in PD selectively involves neuromelanin in substantia nigra (SN) neurons; (ii) decreased availability of glutathione (GSH) and other antioxidant substances; (iii) increase of lipid peroxidation products and reactive oxygen (O2)species (ROS); and (iv) impaired mitochondrial electron transport mechanisms. Most of these changes appear to be closely related to interactions between iron and neuromelanin, which result in accumulation of iron and a continuous production of cytotoxic species leading to neuronal death. Some of these findings have been reproduced in animal models using 6-hydroxydopamine, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), iron loading and beta-carbolines, although none of them is an accurate model for PD in humans. Although it is not clear whether iron accumulation and oxidative stress are the initial events causing cell death or consequences of the disease process, therapeutic efforts aimed at preventing or at least delaying disease progression by reducing the overload of iron and generation of ROS may be beneficial in PD and related neurodegenerative disorders. Current pharmacotherapy of PD, in addition to symptomatic levodopa treatment, includes 'neuroprotective' strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase inhibitors and other antioxidants or free radical scavengers. In the future, these agents could be used in combination with, or partly replaced by, iron chelators and lazaroids that prevent iron-induced generation of deleterious substances. Although experimental and preclinical data suggest the therapeutic potential of these drugs, their clinical applicability will be a major challenge for future research.