Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction.
Manganese ethylene-bis-dithiocarbamate (Mn-EBDC) is the major active element of maneb, a pesticide linked to parkinsonism in certain individuals upon chronic exposure. Additionally, it has been shown to produce dopaminergic neurodegeneration in mice systemically coexposed to another pesticide, 1,1'-dimethyl-4,4'-bipyridinium (paraquat). Here, we described a rat model in which selective dopaminergic neurodegeneration was produced by delivering Mn-EBDC directly to the lateral ventricles. After establishing this model, we tested whether Mn-EBDC provoked dopamine efflux in the striatum, a well-known phenomenon produced by the mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that causes parkinsonism in humans, as well as in some animals. Finally, we investigated whether Mn-EBDC directly inhibited mitochondrial function in vitro using isolated brain mitochondria. Our data demonstrated that Mn-EBDC induced extensive striatal dopamine efflux that was comparable with that induced by MPP+, and that Mn-EBDC preferentially inhibited mitochondrial complex III. As mitochondrial dysfunction is pivotal in the pathogenesis of Parkinson's disease (PD), our results support the proposal that exposure to pesticides such as maneb, or other naturally occurring compounds that inhibit mitochondrial function, may contribute to PD development.
Zhang
Jing
J
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. zhangj@u.washington.edu
Fitsanakis
Vanessa A
VA
Gu
Guangyu
G
Jing
Deqiang
D
Ao
Mingfang
M
Amarnath
Venkataraman
V
Montine
Thomas J
TJ
D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005028:Ethylenebis(dithiocarbamates) / Q000633:toxicity; D005110:Extracellular Space / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009942:Organometallic Compounds / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D005028:Ethylenebis(dithiocarbamates); D017895:Manganese Compounds; D009498:Neurotoxins; D009942:Organometallic Compounds; C471036:manganese ethylenebis(dithiocarbamate); C471037:copper ethylenebis(dithiocarbamate); D004298:Dopamine