Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease

Abstract

In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per sc. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).

The Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease

“…The ethylenebisdithiocarbamate anion and not the manganese moiety of MB appears to be the active component (Soleo et al, 1996) and possesses chelating properties. Thus, it could chelate metals such as iron, which have been shown to accumulate in brains of PD patients (Lan and Jiang, 1997). These possibilities are consistent with the assertion that targeting multiple sites of the nigrostriatal DA system may impede homeostatic reregulation, resulting in toxicity.…”

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…DMF exerts beneficial effects in preclinical models of neuroinflammation and neurodegeneration (59); protects SH-SY5Y cells against 6-hydroxydopamine-induced neurotoxicity and the brain from oxidative stress via Nrf-2-dependent mechanisms (31). Moreover, DMF was shown to reduce MPTP-induced degeneration of the DA tract (38). In light of what has been mentioned earlier, our study was designed to evaluate the ability of DMF to protect mouse nigrostriatal neurons from MPTP-induced neurotoxicity and neuroinflammation.…”

Iron and Paraquat as Synergistic Environmental Risk Factors in Sporadic Parkinson's Disease Accelerate Age-Related Neurodegeneration

“…In dopaminergic neurons, accessible ferrous iron can react with H 2 O 2 produced during oxidative deamination of dopamine to produce highly reactive hydroxyl radicals, which in turn can damage proteins, nucleic acids, and membrane phospholipids leading to cellular degeneration (Jellinger et al, 1993;Jenner, 2003;Zecca et al, 2004). Furthermore, elevated iron is able to catalyze Parkinsonism-inducing neurotoxin MPTP to MPP ϩ (1-methyl-4-phenylpyridium ion) in solution producing reactive oxygen species as by-products of the reaction (Poirier et al, 1985) and sequentially lead to lipid peroxidation and dopaminergic neuron death within the SN, suggesting that high a concentration of iron can contribute to the toxicity of the compound (Lan and Jiang, 1997). However, iron chelation via either genetic expression of the iron-binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol attenuates MPTPmediated biochemical, neuropathological, and behavioral deficits (Kaur et al, 2003).…”