title: Inflaming the diseased brain: a role for tainted melanins.
abstract: Inflammation plays a crucial role in neurodegenerative diseases, but the irritants responsible for this response remain largely unknown. This report addressed the hypothesis that hypochlorous acid reacts with dopamine to produce melanic precipitates that promote cerebral inflammation. Spectrophotometric studies demonstrated that nM amounts of HOCl and dopamine react within seconds. A second-order rate constant for the reaction of HOCl and dopamine of 2.5 × 10(4)M(-1)s(-1) was obtained by measuring loss of dopaminergic fluorescence due to HOCl. Gravimetric measurements, electron microscopy, elemental analysis, and a novel use of flow cytometry confirmed that the major product of this reaction is a precipitate with an average diameter of 1.5 μm. Flow cytometry was also used to demonstrate the preferential reaction of HOCl with dopamine rather than albumin. Engulfment of the chlorodopamine particulates by phagocytes in vitro caused these cells to release TNFα and die. Intrastriatal administration of 10(6) particles also increased the content of TNFα in the brain and led to a 50% loss of the dopaminergic neurons in the nigra. These studies indicate that HOCl and dopamine react quickly and preferentially with each other to produce particles that promote inflammation and neuronal death in the brain.
authors.affiliation: Department of Neurosciences, Winthrop University Hospital, Mineola, NY 11501, USA. Electronic address: Thomas_Jeitner@nymc.edu.
authors.forename: T M
authors.initials: TM
authors.lastname: Jeitner
authors.affiliation: Department of Neurosciences, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kalogiannis
authors.affiliation: Department of Outcomes Research, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Patrick
authors.affiliation: Department of Geriatrics, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: I
authors.initials: I
authors.lastname: Gomolin
authors.affiliation: Department of Vascular Biology, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: T
authors.initials: T
authors.lastname: Palaia
authors.affiliation: Department of Vascular Biology, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ragolia
authors.affiliation: Department of Outcomes Research, Winthrop University Hospital, Mineola, NY 11501, USA.
authors.forename: D
authors.initials: D
authors.lastname: Brand
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Delikatny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D045744:Cell Line, Tumor; D004298:Dopamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010587:Phagocytosis; D013053:Spectrophotometry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D008543:Melanins; D014409:Tumor Necrosis Factor-alpha; C050034:2-chlorodopamine; D006997:Hypochlorous Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Brain; Dopamine; Hypochlorous acid; Inflammation; Parkinson disease