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

Keuters, Meike HedwigKeksa-Goldsteine, VeltaDhungana, HiramaniHuuskonen, Mikko T.Pomeshchik, YuriySavchenko, EkaterinaKorhonen, Paula K.Singh, YajuvinderWojciechowski, SaraLehtonen, SarkaKanninen, Katja M.Malm, TarjaSirviö, JouniMuona, AnuKoistinaho, MillaGoldsteins, GundarsKoistinaho, Jari2021-10-062021-10-062021-02-10Keuters, M H, Keksa-Goldsteine, V, Dhungana, H, Huuskonen, M T, Pomeshchik, Y, Savchenko, E, Korhonen, P K, Singh, Y, Wojciechowski, S, Lehtonen, S, Kanninen, K M, Malm, T, Sirviö, J, Muona, A, Koistinaho, M, Goldsteins, G & Koistinaho, J 2021, 'An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo', Scientific Reports, vol. 11, no. 1, 3518. https://doi.org/10.1038/s41598-021-81741-3ORCID: /0000-0003-4216-1024/work/101084202http://hdl.handle.net/10138/334982Lipid 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.14engcc_byinfo:eu-repo/semantics/openAccessFOCAL CEREBRAL-ISCHEMIACELL-DEATH MECHANISMSOXIDATIVE STRESSEMBOLIC STROKEANIMAL-MODELSMOUSE MODELMINOCYCLINEBRAINIRONGLUTATHIONEBiomedicineAn arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivoArticleopenAccessfa333a52-18e7-4277-baa7-4480675b0b9b000684770600014