title: Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons.
abstract: Inflammation is a common feature of Parkinson Disease and other neurodegenerative disorders. Hypochlorous acid (HOCl) is a reactive oxygen species formed by neutrophils and other myeloperoxidase-containing cells during inflammation. HOCl chlorinates the amine and catechol moieties of dopamine to produce chlorinated derivatives collectively termed chlorodopamine. Here, we report that chlorodopamine is toxic to dopaminergic neurons both in vivo and in vitro Intrastriatal administration of 90 nmol chlorodopamine to mice resulted in loss of dopaminergic neurons from the substantia nigra and decreased ambulation-results that were comparable to those produced by the same dose of the parkinsonian poison, 1-methyl-4-phenylpyridinium (MPP+). Chlorodopamine was also more toxic to differentiated SH SY5Y cells than HOCl. The basis of this selective toxicity is likely mediated by chlorodopamine uptake through the dopamine transporter, as expression of this transporter in COS-7 cells conferred sensitivity to chlorodopamine toxicity. Pharmacological blockade of the dopamine transporter also mitigated the deleterious effects of chlorodopamine in vivo The cellular actions of chlorodopamine included inactivation of the α-ketoglutarate dehydrogenase complex, as well as inhibition of mitochondrial respiration. The latter effect is consistent with inhibition of cytochrome c oxidase. Illumination at 670 nm, which stimulates cytochrome c oxidase, reversed the effects of chlorodopamine. The observed changes in mitochondrial biochemistry were also accompanied by the swelling of these organelles. Overall, our findings suggest that chlorination of dopamine by HOCl generates toxins that selectively kill dopaminergic neurons in the substantia nigra in a manner comparable to MPP+.
authors.affiliation: *Department of Biochemistry and Molecular Biology, New York Medical College, Basic Science, Valhalla, NY 10595; Department of Biomedical Research thomas_jeitner@nymc.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Jeitner
authors.affiliation: Department of Biomedical Research.
authors.forename: Mike
authors.initials: M
authors.lastname: Kalogiannis
authors.affiliation: Department of Biomedical Research.
authors.forename: Boris F
authors.initials: BF
authors.lastname: Krasnikov
authors.affiliation: Department of Geriatrics, Winthrop University Hospital, Mineola, NY 11501;
authors.forename: Irving
authors.initials: I
authors.lastname: Gomolin
authors.affiliation: Department of Biomedical Research.
authors.forename: Morgan R
authors.initials: MR
authors.lastname: Peltier
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin - Milwaukee, Milwaukee, WI 53211.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Moran
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D006997:Hypochlorous Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine
keywords: Parkinson Disease; brain; dopamine; hypochlorous acid; neuroinflammation