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Title: | Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation | Authors: | SPAAS, Jan FRANSSEN, Wouter KEYTSMAN, Charly Blancquaert, Laura VANMIERLO, Tim BOGIE, Jeroen BROUX, Bieke HELLINGS, Niels VAN HORSSEN, Jack Posa, Dheeraj Kumar Hoetker, David Baba, Shahid P. Derave, Wim OP 'T EIJNDE, Bert |
Issue Date: | 2021 | Publisher: | BMC | Source: | JOURNAL OF NEUROINFLAMMATION, 18 (1) (Art N° 255) | Abstract: | Background: Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. Methods: The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). Results: Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (beta-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were similar to twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. Conclusions: Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS. | Notes: | Spaas, J (corresponding author), Univ MS Ctr UMSC Hasselt Pelt, Hasselt, Belgium.; Spaas, J (corresponding author), Hasselt Univ, Fac Med & Life Sci, BIOMED Biomed Res Inst, Hasselt, Belgium. jan.spaas@uhasselt.be |
Keywords: | Acrolein;Carnosine;Multiple sclerosis;Neuro;inflammation;Oxidative stress;Reactive carbonyl | Document URI: | http://hdl.handle.net/1942/35863 | e-ISSN: | 1742-2094 | DOI: | 10.1186/s12974-021-02306-9 | ISI #: | WOS:000714933500001 | Rights: | The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
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s12974-021-02306-9.pdf | Published version | 6.82 MB | Adobe PDF | View/Open |
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