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

Abstract

Extensive epidemiological data in humans and studies in animal models of Parkinson's disease (PD) suggest that sporadic forms of the disorder are not strictly genetic in nature but most likely because of combined environmental exposures over the period of the life-span coupled with increased genetic susceptibilities. Environmental paraquat and neonatal iron exposure have both been separately suggested as potential risk factors for sporadic forms of the disease. In this study, we demonstrate that combined environmental exposure to these two agents results in accelerated age-related degeneration of nigrostriatal dopaminergic neurons. Furthermore, pretreatment with the synthetic superoxide dismutase/catalase mimetic, EUK-189, significantly attenuated neuronal death mediated by combined paraquat and iron treatment. These findings support the notion that environmental PD risk factors may act synergistically to produce neurodegeneration associated with the disorder and that iron and paraquat may act via common oxidative stress-mediated mechanisms.

The Effects of Polyphenols on Survival and Locomotor Activity in Drosophila melanogaster Exposed to Iron and Paraquat

“…Similar survival rates were observed with GA and EGC (data not shown). These data comply with the notion that iron exacerbates paraquat-induced toxicity in in vivo [54], but the capability of polyphenols to form iron-complexes and to scavenge free radicals might protect dopaminergic neurons from PQ-induced O 2 Á-and H 2 O 2 harmful effects (e.g., Fenton reaction). Consequently, dopaminergic neurons might conserve their functionality.…”

Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration

“…This "hit and run" mechanism would also be compatible with the absence of influenza viral RNA detection in archival brain tissue of postencephalic parkinsonian patients as reported by McCall et al (36), because by the time the patient had passed away, the acute viral infection would have been resolved. Thus, if one accepts that influenza can activate the innate CNS immune system (43,44) and induce a modest loss of neurons, there would be the necessity of a second hit that would lead to development of additional neuronal loss passing the threshold necessary for induction of parkinsonian symptoms (45) that would not have occurred without the priming that occurs via the influenza infection (46). In conclusion, we find that the highly infectious, neurotropic A/Vietnam/1203/04 (H5N1) inf luenza virus progresses from the peripheral nervous system into the CNS, where it activates the innate immune response in the brain.…”

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

“…When exposed to free radicals or excess iron, a-synuclein aggregates and induces the aggregation of additional molecules due to the redox-active nature of these aggregates, creating an environment of ongoing oxidative stress (149,332). In transfected cell lines, co-expression of DMT1 with wild-type or mutant asynuclein enhances toxicity of the latter (84), and oral administration of excess iron to neonatal or early post-natal mice predisposes these animals to MPTP and paraquat induced PD (220,343,367). Iron-fed mice show significantly more DA toxicity relative to controls, indicating that excess iron increases the vulnerability of DA neurons to toxic insults (220).…”