Serotonin as a putative scavenger of hypohalous acid in the brain

Abstract

Neurodegenerative disorders represent the culmination of numerous insults including oxidative stress. The long etiology of most of these disorders suggests that lessening the effects of one of more of the insults could significantly delay disease onset. Antioxidants have been tested as possible therapeutics for neurodegenerative disorders, but with little success. Here we report that serotonin acts as a scavenger of hypochlorous acid (HOCl) in the brain. Serotonin was shown to prevent the oxidation of 2-thio-5-nitrobenzoate by HOCl in a biphasic manner. The first phase was a partial scavenging that occurred at concentrations of serotonin that exceeded those of HOCl. 1H-NMR studies indicated that HOCl chlorinates both the aryl and akyl nitrogen atoms of serotonin. Thus, the residual but lower oxidation of 2-thio-5-nitrobenzoate that occured during the first phase of scavenging is likely to due to formation of serotonergic chloramines. A second phase of scavenging occurred at concentrations of HOCl that exceeded those of serotonin. Under these conditions, the chlorinated serotonin polymerized and formed inert aggregates. Serotonin was further shown to prevent the loss of cells and cellular α-ketoglutarate dehydrogenase activity caused by HOCl. Extracellular concentrations of serotonin in the brain can be elevated with selective serotonin reuptake inhibitors and suggests that such compounds could be used to increase the cerebral antioxidant capacity. Acute administration of selective serotonin reuptake inhibitors to mice treated with endotoxin partially mitigated sickness behavior and protein chlorination in the brain. These observations suggest that serotonin may act to suppress chlorinative stress in the brain.

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

“…However, intrastriatal administration of chlorodopamine resulted in loss of dopaminergic neurons and decreased locomotor activity in mice in a manner similar as observed for the Parkinsonian toxin MPP + [53]. Selective serotonin reuptake inhibitors ameliorated LPS-induced sickness behavior in wt mice [25], a potential result of HOCl scavenging by serotonin which is a high-affinity substrate for MPO-mediated oxidation [25]. The fact that brains of transgenic APP/PS1 mice contain far higher HOCl concentrations as compared to wt littermates makes it conceivable that MPO derived oxidants have the potential to contribute to induce behavioral and cognitive deficits [54].…”

“…Activation of the immune system during systemic inflammation can induce sickness behavior [23] and forced expression of human MPO in a murine Parkinson's Disease model exacerbates motor impairment [24]. HOCl scavengers were suggested to modulate sickness/motor behavior in a murine model of inflammation [25]. To study this aspect more directly we monitored the effects of low-grade inflammation on metabolic, physiological, and behavioral activities of wt and MPO −/− animals.…”

Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation

“…There are three major known pathways of melatonin degradation: (a) the classical hepatic catabolic pathway that generates 6-hydroxymelatonin that is then excreted via the kidney as a sulphate conjugate [ 3 , 5 , 25 , 26 ]; (b) the alternative indolic pathway that produces 5-methoxyindole acetic acid or 5-methoxytryptophol [ 27 , 28 ]; and (c) the kynuric pathway that produces N 1 -acetyl-N 2 -formyl-5-kynuramine (AFMK) [ 29 – 31 ]. In addition to the antioxidant properties of melatonin, AFMK and N 1 -acetyl-5-methoxykinuramine (AMK) are two important melatonin metabolites that have excellent radical scavenging activity [ 5 , 32 , 33 ].…”

The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory

“…Serotonin has antioxidant properties in vitro and an animal model of serotonin deficiency shows reduced antioxidant capacity . Moreover, serotonin promotes the differentiation of neurons and glia, and the formation of synapses .…”