Altered Brain Metabolism of Iron as a Cause of Neurodegenerative Diseases?

Abstract

Iron is the most abundant metal in the human body (Pollitt and Leibel, 1982; Youdim, 1988), and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). Within the brain, iron shows an uneven distribution, with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, and globus pallidus), red nucleus, and dentate nucleus (Spatz, 1922; Hallgren and Sourander, 1958; Hill and Switzer, 1984; Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not hemosiderin (Hallgren and Sourander, 1958; Octave et al., 1983), with relatively little in a free and reactive form. Although the function of a regionally high brain iron content is unknown, the homeostasis of brain iron is thought to be necessary for normal brain function, especially in learning and memory (Youdim et al., 1989; Yehuda and Youdim, 1989; Pollit and Metallinos‐Katsaras, 1990; Youdim, 1990). Thus, a high content of brain iron may be essential, particularly during development, but its presence means that injury to brain cells may release iron ions that can lead to oxidative stress via formation of oxygen free radicals. Such radicals are thought to be involved in lipid peroxidation of the cell membrane, leading to increased membrane fluidity, disturbance of calcium homeostasis, and finally cell death (Youdim et al., 1989; Halliwell, 1992). Iron is an essential participant in many metabolic processes, including (a) DNA, RNA, and protein synthesis, (b) as a cofactor of many heme and nonheme enzymes, (c) the formation of myelin, and (d) the development of the neuronal dendritric tree (Ben‐Shachar et al., 1986; Youdim et al., 1991b). A deficiency of iron metabolism would therefore be expected to alter some or all of these processes (Jacobs and Worwood, 1980; Youdim, 1985, 1988). Studies of iron distribution in the human brain have demonstrated that the degree of iron deposition, primarily in the basal ganglia (a predominantly dopamine structure), increases with age (Hallgren and Sourander, 1958) and in certain disorders, most notably the basal ganglia disorders (Seitelberger, 1964). This review will present some of the experimental evidence indicating a role of disturbed iron metabolism as a cause of the neurodegenerative disorder Parkinson's disease and possibly other neurodegenerative disorders such as Alzheimer's disease. In addition, some of the neurochemical and histochemical findings obtained at autopsy from analyses of the brain from patients with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and progressive supranuclear palsy (Steele‐Richardson‐Olszewski's disease) will be discussed. Special attention will be paid to clarifying the possible implication of the observed changes in the etiology of neurodegenerative disorders.

Understanding the human health effects of chemical mixtures.

“…Savolainen et al (79) attribute these actions to lead amplification of neurotransmitter-induced ROS generation, plus an effect of lead to reduce cellular glutathione levels. Iron has been suggested to be a factor in neurodegenerative diseases, especially in Parkinson's disease, on the basis of the observation that levels of iron are elevated in the parkinsonian substantia nigra and that iron induces oxidative stress (80,81). Gerlach et al (81) also report elevated iron levels in the caudate, but not the nigra, in the association centers, hippocampus, and basal forebrain in Alzheimer's disease.…”

Modulation of oxidative events by multivalent manganese complexes in brain tissue

“…In spite of extensive research efforts, the evidence for such speculations of manganese pro-oxidant activity, based primarily on use of the divalent salt manganese chloride (MnCl 2 ), has been conflicting. Manganese has been implicated in enhancing dopamine auto-oxidation and oxidative nigral [10,[13][14][15], and in inflicting damage similar to that of other mitochondrial toxins such as carbon monoxide and cyanide [16]. In evaluations of the oxidative character of manganese, several groups have attributed accelerated ROS formation to both the divalent and trivalent states of the metal [17,18].…”

Pro- or anti-oxidant manganese: a suggested mechanism for reconciliation

“…Manganese-induced brain lesions tend to occur in regions of intense oxygen consumption (Yamada et al, 1986), and are marked by enhanced auto-oxidation and turnover of dopamine, losses of neurons and demyelination (Cotzias et al, 1971;Donaldson et al, 1984;Gerlach et al, 1994;Erikson et al, 1987). The site-specificity of the pathology and the selective targeting of dopamine have led to the comparison of manganese-induced neurodegeneration to that of other transition metals, iron and copper (Triggs and Willmore, 1984;Rauhala and Chiueh, 2000;Sengstock et al, 1993), i.e.…”