Iron and paraquat as synergistic environmental risk factors in sporadic Parkinson's disease accelerate age-related neurodegeneration.
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.
Peng
Jun
J
Buck Institute for Age Research, Novato, California 94945, USA.
Peng
Li
L
Stevenson
Fang Feng
FF
Doctrow
Susan R
SR
Andersen
Julie K
JK
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004357:Drug Synergism; D004781:Environmental Exposure / Q000009:adverse effects*; D006540:Herbicides / Q000633:toxicity; D007501:Iron / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D012459:Salicylates / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism
C436526:EUK-189; D006540:Herbicides; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D012459:Salicylates; D007501:Iron; D013482:Superoxide Dismutase; D010269:Paraquat