An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
Meike Hedwig Keuters, Velta Keksa-Goldsteine, Hiramani Dhungana, Mikko T. Huuskonen, Yuriy Pomeshchik, Ekaterina Savchenko, Paula Korhonen, Yajuvinder Singh, Sara Wojciechowski, Šárka Lehtonen, Katja M. Kanninen, Tarja Malm, Jouni Sirviö, Anu Muona, Milla Koistinaho, Gundars Goldsteins, Jari Koıstınaho
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.