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Microglia is particularly efficient phagocytosing cells that undergo programmed cell death (apoptosis) in physiological conditions. However, mounting evidence suggests microglial phagocytosis dysfunction in multiple brain disorders. These observations prompted us to search for phagocytosis modulators (enhancers or inhibitors) with therapeutic potential. We used a bottom\u2010up strategy that consisted on the identification of phagocytosis modulators using phenotypic high throughput screenings (HTSs) in cell culture and validation in organotypic cultures and in vivo. We performed two complementary HTS campagnes: at Achucarro, we used primary cultures of mouse microglia and compounds of the Prestwick Chemical Library; at Roche, we used human iPSC derived macrophage\u2010like cells and a proprietary chemo\u2010genomic library with 2200 compounds with known mechanism\u2010of\u2010action. Next, we validated the more robust compounds using hippocampal organotypic cultures and identified two phagocytosis inhibitors: trifluoperazine, a dopaminergic and adrenergic antagonist used as an antipsychotic and antineoplastic; and deoxytubercidin, a ribose derivative. Finally, we tested whether these compounds were able to modulate phagocytosis of apoptotic newborn cells in the adult hippocampal neurogenic niche in vivo by administering them into the mouse hippocampus using osmotic minipumps. We confirmed that both trifluoperazine and deoxytubercidin have anti\u2010phagocytic activity in vivo, and validated our bottom\u2010up strategy to identify novel phagocytosis modulators. These results show that chemical libraries with annotated mechanism of action are an starting point for the pharmacological modulation of microglia in drug discovery projects aiming at the therapeutic manipulation of phagocytosis in brain diseases.<\/jats:p>","DOI":"10.1002\/glia.24637","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T09:39:38Z","timestamp":1730713178000},"page":"330-351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A bottom\u2010up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-9608","authenticated-orcid":false,"given":"Noelia","family":"Rodriguez\u2010Iglesias","sequence":"first","affiliation":[{"name":"Glial Cell Biology Lab Achucarro Basque Center for Neuroscience  Leioa Spain"},{"name":"Department of Neuroscience University of the Basque Country EHU\/UPV  Leioa Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-0277","authenticated-orcid":false,"given":"I\u00f1aki","family":"Paris","sequence":"additional","affiliation":[{"name":"Glial Cell Biology Lab Achucarro Basque Center for Neuroscience  Leioa Spain"},{"name":"Department of Neuroscience University of the Basque Country EHU\/UPV  Leioa Spain"},{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel F. 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