Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-81741-3
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Funding
- Marie Skodowska-Curie Initial Training Network (ITN) nEUROinflammation - European Commission [607962]
- Aranda Pharma Ltd [ADA-409-052]
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ADA-409-052 is a small molecule that inhibits lipid peroxidation and protects against ferroptotic cell death in neuronal cells. It also suppresses pro-inflammatory activation of microglia and reduces infarct volume and expression of pro-inflammatory genes in a mouse model of stroke. Targeting ferroptosis may be a promising therapeutic strategy for neurological diseases involving severe neuronal death and neuroinflammation.
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.
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