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 × 104 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 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 and to produce particles that promote inflammation and neuronal death in the brain.

Serotonin as a putative scavenger of hypohalous acid in the brain

“…These cells phagocytosed the aggregates no increase in released LDH was observed. In contrast, the addition of the same amount of chlorodopamine aggregates to THP-1 cell resulted in cell death and LDH release consistent with our previous studies [23]. …”

“…Changes observed in the UV-visible spectra of chlorinated 5HT at 274 nm and higher wavelengths are indicative of the formation of polymers based on our observations of other chlorinated aromatic neurotransmitters [23]. The possibility that chlorinated 5HT forms polymers and aggregates, was suggested by the precipitation observed in aqueous mixtures of 10 −2 M amounts of 5HT and HOCl and confirmed by light microscopy (data not shown).…”

“…The dimerization consumes superoxide and 5HT radicals and led Huether and his colleagues to propose that 5HT was a radical scavenger [22]. Dimers represent the simplest polymers and in our preliminary experiments we noted that the reaction of 5HT and HOCl produced precipitates indicative of polymer formation [23]. These observations suggested the possibility that 5HT acted as a scavenger of HOCl, which is supported by the studies of Sariahmetoglu et al .…”

“…2). These reactions were carried out in the presence of deuterated methanol to prevent the precipitation of the reaction products in aqueous buffers [26]. The 1 H NMR spectrum of 10 mM 5HT in deuterated methanol is shown in Figure 2A.…”

“…The possibility that chlorinated 5HT forms polymers and aggregates, was suggested by the precipitation observed in aqueous mixtures of 10 −2 M amounts of 5HT and HOCl and confirmed by light microscopy (data not shown). These aggregates which were examined further using flow cytometry [23]. …”