An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo

Abstract Lipid peroxidation-initiated ferroptosis is an iron-dependent mechanism of programmed cell death taking place in neurological diseases. Here we show that a condensed benzo[b]thiazine derivative small molecule with an arylthiazine backbone (ADA-409-052) inhibits tert-Butyl hydroperoxide (TBH...

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Autores principales: Meike Hedwig Keuters, Velta Keksa-Goldsteine, Hiramani Dhungana, Mikko T. Huuskonen, Yuriy Pomeshchik, Ekaterina Savchenko, Paula K. Korhonen, Yajuvinder Singh, Sara Wojciechowski, Šárka Lehtonen, Katja M. Kanninen, Tarja Malm, Jouni Sirviö, Anu Muona, Milla Koistinaho, Gundars Goldsteins, Jari Koistinaho
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:3ca87910b4fe497bb6a795384b53ddb22021-12-02T14:11:29ZAn arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo10.1038/s41598-021-81741-32045-2322https://doaj.org/article/3ca87910b4fe497bb6a795384b53ddb22021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81741-3https://doaj.org/toc/2045-2322Abstract Lipid peroxidation-initiated ferroptosis is an iron-dependent mechanism of programmed cell death taking place in neurological diseases. Here we show that a condensed benzo[b]thiazine derivative small molecule with an arylthiazine backbone (ADA-409-052) inhibits tert-Butyl hydroperoxide (TBHP)-induced lipid peroxidation (LP) and protects against ferroptotic cell death triggered by glutathione (GSH) depletion or glutathione peroxidase 4 (GPx4) inhibition in neuronal cell lines. In addition, ADA-409-052 suppresses pro-inflammatory activation of BV2 microglia and protects N2a neuronal cells from cell death induced by pro-inflammatory RAW 264.7 macrophages. Moreover, ADA-409-052 efficiently reduces infarct volume, edema and expression of pro-inflammatory genes in a mouse model of thromboembolic stroke. Targeting ferroptosis may be a promising therapeutic strategy in neurological diseases involving severe neuronal death and neuroinflammation.Meike Hedwig KeutersVelta Keksa-GoldsteineHiramani DhunganaMikko T. HuuskonenYuriy PomeshchikEkaterina SavchenkoPaula K. KorhonenYajuvinder SinghSara WojciechowskiŠárka LehtonenKatja M. KanninenTarja MalmJouni SirviöAnu MuonaMilla KoistinahoGundars GoldsteinsJari KoistinahoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Meike Hedwig Keuters
Velta Keksa-Goldsteine
Hiramani Dhungana
Mikko T. Huuskonen
Yuriy Pomeshchik
Ekaterina Savchenko
Paula K. Korhonen
Yajuvinder Singh
Sara Wojciechowski
Šárka Lehtonen
Katja M. Kanninen
Tarja Malm
Jouni Sirviö
Anu Muona
Milla Koistinaho
Gundars Goldsteins
Jari Koistinaho
An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
description Abstract Lipid peroxidation-initiated ferroptosis is an iron-dependent mechanism of programmed cell death taking place in neurological diseases. Here we show that a condensed benzo[b]thiazine derivative small molecule with an arylthiazine backbone (ADA-409-052) inhibits tert-Butyl hydroperoxide (TBHP)-induced lipid peroxidation (LP) and protects against ferroptotic cell death triggered by glutathione (GSH) depletion or glutathione peroxidase 4 (GPx4) inhibition in neuronal cell lines. In addition, ADA-409-052 suppresses pro-inflammatory activation of BV2 microglia and protects N2a neuronal cells from cell death induced by pro-inflammatory RAW 264.7 macrophages. Moreover, ADA-409-052 efficiently reduces infarct volume, edema and expression of pro-inflammatory genes in a mouse model of thromboembolic stroke. Targeting ferroptosis may be a promising therapeutic strategy in neurological diseases involving severe neuronal death and neuroinflammation.
format article
author Meike Hedwig Keuters
Velta Keksa-Goldsteine
Hiramani Dhungana
Mikko T. Huuskonen
Yuriy Pomeshchik
Ekaterina Savchenko
Paula K. Korhonen
Yajuvinder Singh
Sara Wojciechowski
Šárka Lehtonen
Katja M. Kanninen
Tarja Malm
Jouni Sirviö
Anu Muona
Milla Koistinaho
Gundars Goldsteins
Jari Koistinaho
author_facet Meike Hedwig Keuters
Velta Keksa-Goldsteine
Hiramani Dhungana
Mikko T. Huuskonen
Yuriy Pomeshchik
Ekaterina Savchenko
Paula K. Korhonen
Yajuvinder Singh
Sara Wojciechowski
Šárka Lehtonen
Katja M. Kanninen
Tarja Malm
Jouni Sirviö
Anu Muona
Milla Koistinaho
Gundars Goldsteins
Jari Koistinaho
author_sort Meike Hedwig Keuters
title An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
title_short An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
title_full An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
title_fullStr An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
title_full_unstemmed An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
title_sort arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/3ca87910b4fe497bb6a795384b53ddb2
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