Serotonin as a Putative Scavenger of Hypohalous Acid in the Brain
Open accessAbstract
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 or 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. (1)H-NMR studies indicated that HOCl chlorinates both the aryl and akyl nitrogen atoms of serotonin. Thus, the oxidation of 2-thio-5-nitrobenzoate that occurred during the first phase of scavenging is likely due to the 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 complex 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.
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Biogenic amines, mostly through chloramine formation, have been demonstrated to serve as biomolecular targets of chlorination stress including histamine, serotonin, melatonin, and taurine.
“biogenic amines, mostly through chloramine formation, have been demonstrated to serve as biomolecular targets of chlorination stress including histamine, serotonin, melatonin, and taurine among others (90, 91).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [91]
Antagonists of MPO enzymatic activity such as the synthetic MPO inhibitor verdiperstat or the endogenous metabolite uric acid, blocking HOCl formation, have been explored for pharmacological control of pathophysiological chlorination stress.
“antagonists of MPO enzymatic activity (such as the synthetic MPO inhibitor verdiperstat or the endogenous metabolite uric acid) blocking HOCl formation have been explored for pharmacological control of pathophysiological chlorination stress (47, 62, 91, 103–109).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [91]
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Santos, A. L., & Lindner, A. B. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/5716409 · Cited by 225 · see citing works
“Furthermore, selective serotonin reuptake inhibitors, such as fluoxetine, reduce protein chlorination in the brain, suggesting a potential therapeutic approach against age-related protein chlorination effects [160].”
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Linking Inflammation and Parkinson Disease: Hypochlorous Acid Generates Parkinsonian Poisons
Jeitner, T. M., Kalogiannis, M., Krasnikov, B. F., Gomlin, I., Peltier, M. R., & Moran, G. R. (2016) · Toxicological Sciences · doi:10.1093/toxsci/kfw052 · Cited by 78 · see citing works
“The magnitude of these losses was comparable to those reported earlier (Kalogiannis et al. 2016, Whiteman et al., 2005a) and conformed to a 4-parameter logistic curve (R2¼1.00) with an EC50¼30.1 lM. Chlorodopamine was prepared by mixing HOCl and dopamine in prewarmed HBSS 1 min prior the addition…”
ResultInfluentialMelatonin: Protection against age-related cardiac pathology
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“In addition, biogenic amines, mostly through chloramine formation, have been demonstrated to serve as biomolecular targets of chlorination stress including histamine, serotonin, melatonin, and taurine among others (90, 91).”
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“BDNF has been used in mouse models of traumatic brain injury (TBI) (Kim et al., 2016) and spinal cord injury (Robinson and Lu, 2017) to support the survival of neural stem cells, their differentiation into neurons, and possible integration into neural circuits.”
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“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].”
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“…plasma albumin extravasation, elevated synthesis of endothelial nitric oxide, heightened levels of platelet activating factor (PAF) levels [47], and rising concentrations of brain-derived neurotrophic factor (BDNF) [48], calcitonin gene-related peptide (CGRP) [49], and serotonin in the serum [50].”
BackgroundTranslation and Post-translational Modifications in Protein Biosynthesis
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Fluoxetine Protects Retinal Ischemic Damage in Mice
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“L-dopa adverse effects in serotonergic neurons would be enhanced due to serotonin depletion in AADC-DY since serotonin is known to exert antioxidant and neuroprotective effects [134, 135].”
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- Authors
- Kalogiannis, M., Delikatny, E. J., & Jeitner, T. M.
- Affiliations
- Winthrop-University Hospital (US)
- University of Pennsylvania (US)
- Corresponding author
- Jeitner, Thomas M.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 1862
- Issue
- 4
- Pages
- 651-661
- ISSN
- 0925-4439 (ISSN-L)
- PMC
- PMC4820265
- OpenAlex
- W2269085706
- Cited by
- 19
- References
- 69
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R03NS074286)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- serotonin, hypochlorous acid, hypohalous acids, oxidative stress, neurodegenerative diseases, antioxidant defense, chlorination, alpha-ketoglutarate dehydrogenase, selective serotonin reuptake inhibitors, endotoxin, sickness behavior, brain
- MeSH terms
- THP-1 Cells, Animals, Brain, Humans, Hypochlorous Acid, Ketoglutarate Dehydrogenase Complex, Male, Serotonin, Free Radical Scavengers, Oxidative Stress, Mice, Halogenation
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