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Neuroinflammation, characterized by the activation of glial cells such as microglia, is closely linked with neurodegenerative pathways and constitutes a major mechanism of neural damage and disease progression. Importantly, inhibition of necroptosis results in disease improvement, unveiling an alternative approach for therapeutic intervention. In the present study, we screened a small library of new molecules, potentially inhibitors of necroptosis, using two cellular models of necroptosis. A new oxazolone, Oxa12, reduced tumour necrosis factor \u03b1 (TNF-\u03b1)-induced necroptosis in mouse L929 fibrosarcoma cells. Notably, Oxa12 strongly inhibited zVAD-fmk-induced necroptosis in murine BV2 microglial cells. Moreover, Oxa12 blocked phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and interfered with necrosome complex formation, indicating that Oxa12 targets components upstream of MLKL. In fact, in silico molecular docking studies revealed that Oxa12 is occupying a region similar to the 1-aminoisoquinoline type II kinase inhibitor inside the receptor-interacting protein 1 (RIP1) kinase domain. Finally, in microglial cells, Oxa12 attenuated zVAD-fmk- and lipopolysaccharide (LPS)-induced inflammatory processes, as revealed by a marked decrease of TNF-\u03b1 and\/or IL-1\u03b2 expression. More specifically, Oxa12 negatively targeted c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, as well as NF-\u03baB activation. Overall, we identified a strong lead inhibitor of necroptosis that is also effective at reducing inflammation-associated events. Oxa12 is a promising candidate molecule for further development to target disease states dependent on RIP kinase activity.<\/jats:p>","DOI":"10.1038\/s41420-018-0067-0","type":"journal-article","created":{"date-parts":[[2018,7,10]],"date-time":"2018-07-10T09:26:05Z","timestamp":1531214765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Phenotypic screening identifies a new oxazolone inhibitor of necroptosis and neuroinflammation"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3433-6712","authenticated-orcid":false,"given":"Sara R.","family":"Oliveira","sequence":"first","affiliation":[]},{"given":"Pedro A.","family":"Dion\u00edsio","sequence":"additional","affiliation":[]},{"given":"Hugo","family":"Brito","sequence":"additional","affiliation":[]},{"given":"L\u00eddia","family":"Franco","sequence":"additional","affiliation":[]},{"given":"Catarina A. 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