Inflaming the diseased brain: a role for tainted melanins

• Published in: Biochimica et biophysica acta 2015-05, Vol.1852 (5), p.937-950
• Main Authors: Jeitner, T.M., Kalogiannis, M., Patrick, P.A., Gomolin, I., Palaia, T., Ragolia, L., Brand, D., Delikatny, E.J.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Chemistry; Cell Line, Tumor; Dopamine; Dopamine - analogs & derivatives; Dopamine - chemistry; Dopamine - metabolism; Dopamine - pharmacology; Halogenation; Humans; Hypochlorous acid; Hypochlorous Acid - chemistry; Hypochlorous Acid - metabolism; Immunohistochemistry; Inflammation; Inflammation - metabolism; Male; Melanins - metabolism; Mice, Inbred C57BL; Microscopy, Electron; Parkinson disease; Phagocytes - drug effects; Phagocytes - metabolism; Phagocytes - ultrastructure; Phagocytosis; Spectrophotometry; Tumor Necrosis Factor-alpha - metabolism; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.01.004

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 × 104M−1s−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 1.5μm. 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 106 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. •HOCl and dopamine react with a second-order rate constant of 2.5 × 104M−1s−1.•The main products of this reaction are precipitates with an diameter of 1.5μm.•Engulfment of the precipitates by phagocytes caused these cells to release TNFα.•Intrastriatal injection of 106 melanic particles also increased TNFα in the brain.•This increase in TNFα was accompanied by a 50% loss of nigral neurons.