title: Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction.
abstract: 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.
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. zhangj@u.washington.edu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Fitsanakis
authors.forename: Guangyu
authors.initials: G
authors.lastname: Gu
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.forename: Mingfang
authors.initials: M
authors.lastname: Ao
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Amarnath
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: 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
chemical_list: D005028:Ethylenebis(dithiocarbamates); D017895:Manganese Compounds; D009498:Neurotoxins; D009942:Organometallic Compounds; C471036:manganese ethylenebis(dithiocarbamate); C471037:copper ethylenebis(dithiocarbamate); D004298:Dopamine