A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors.

Autor: Rodriguez-Iglesias N; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain.; Department of Neuroscience, University of the Basque Country EHU/UPV, Leioa, Spain., Paris I; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain.; Department of Neuroscience, University of the Basque Country EHU/UPV, Leioa, Spain.; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Valero J; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain.; Department of Neuroscience, University of the Basque Country EHU/UPV, Leioa, Spain.; Ikerbasque Foundation, Bilbao, Spain., Cañas-Zabala L; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain.; Department of Neuroscience, University of the Basque Country EHU/UPV, Leioa, Spain., Carretero A; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain., Hatje K; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Zhang JD; Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Patsch C; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Britschgi M; Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Gutbier S; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Sierra A; Glial Cell Biology Lab, Achucarro Basque Center for Neuroscience, Leioa, Spain.; Ikerbasque Foundation, Bilbao, Spain.; Department of Biochemistry and Molecular Biology, University of the Basque Country EHU/UPV, Leioa, Spain.
Jazyk: angličtina
Zdroj: Glia [Glia] 2024 Nov 04. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1002/glia.24637
Abstrakt: Phagocytosis is an indispensable function of microglia, the brain professional phagocytes. 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-up 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-like cells and a proprietary chemo-genomic library with 2200 compounds with known mechanism-of-action. 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-phagocytic activity in vivo, and validated our bottom-up 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.
(© 2024 F. Hoffmann‐La Roche Ltd and The Author(s). GLIA published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: