The possible role of iron in the etiopathology of parkinson's disease

Abstract

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.

Mitochondrial Iron Sequestration in Dopamine‐Challenged Astroglia: Role of Heme Oxygenase‐1 and the Permeability Transition Pore

“…These observations are germane to the pathogenesis of PD and may serve to unify some of the seemingly disparate pathological features of this neurodegenerative disorder: Abnormally high levels of tissue iron have been consistently reported in the substantia nigra and basal ganglia of PD subjects (Riederer et al, 1989;Jellinger et al, 1990;Jenner, 1992;Youdim, 1994). In PD, the excessive iron deposition primarily affects the zona compacta of the substantia nigra and correlates with loss of dopaminergic neurons in this brain region (Youdim et al, 1993;Youdim, 1994;Janetzky et al, 1997). With use of conventional histochemical stains, the excessive nigral iron appears to be predominantly deposited within astrocytes, microglia, macrophages, and microvessels within areas depleted of neuromelanin-containing (dopaminergic) neurons.…”

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…Transition metals are one of the most important factors that produce the reactive oxygen species, and they are implicated in the generation of ROS in various neurodegenerative diseases (Youdim et al, 1993;Deibel et al, 1996). These transition metals mediate the formation of the hydroxyl radical through the iron-catalyzed or copper-catalyzed HaberWeiss reactions (Haber and Weiss, 1934).…”

Differential Cytotoxicity of Mn(II) and Mn(III): Special Reference to Mitochondrial [Fe-S] Containing Enzymes

“…A recent population study has also established that serum Fe concentrations are significantly reduced in IPD patients compared with controls, suggesting a compartment shift in Fe from blood to tissues, including brain (Logroscino et al, 1997). The role of Fe in etiopathology of IPD has been extensively reviewed by Jenner et al (1992) and Youdim et al (1993).…”

“…A recent population study has also established that serum Fe concentrations are significantly reduced in IPD patients compared with controls, suggesting a compartment shift in Fe from blood to tissues, including brain (Logroscino et al, 1997). The role of Fe in etiopathology of IPD has been extensively reviewed by Jenner et al (1992) and Youdim et al (1993).Previous studies from this laboratory have established that Mn-induced neurotoxicities appear to be associated with its interaction with Fe at systemic and cellular levels (Zheng et al, 1998Zheng and Zhao, 2001). Following Mn exposure, there is a predominant influx of Fe from the blood into the cerebrospinal fluid (CSF) and from extracellular matrix to intracellular space Zheng and Zhao, 2001 et al, 1983).…”