Trifluoperazine Hydrochloride

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.

Due to their potential entry into the human body via the food chain, phenothiazine drugs and their metabolites pose specific health hazards, making their detection in edible tissues of paramount importance.In this research endeavor, a highly sensitive multi-residue anal. method has been devised for the detection of phenothiazine drugs and their metabolites in animal-derived food products, utilizing high performance liquid chromatog. tandem mass spectrometry (HPLC-MS/MS).The preparation of samples involved the use of 1‰% formic acid in acetonitrile as the extraction solvent following sample weighing, with multiple extraction steps diligently performed to ensure optimal outcomes.The sample, post-extraction, was directly introduced into the purification column, yielding significant time savings and rendering the process more environmentally sustainable.This procedural step effectively eliminated interfering substances from the sample matrix, including proteins, salts, and phospholipids.Anal. of the extracted samples was conducted through HPLC-MS/MS, employing an electrospray ionization (ESI) ion source.A comprehensive panel of 20 phenothiazine drugs and their metabolites was successfully resolved within a mere 10-min chromatog. run.A robust linear correlation (R2 ≥ 0.99) was attained within a judiciously chosen range of concentrationsMethod validation was meticulously conducted across multiple animal species, including trout, white shrimp, pork, beef and chicken.The developed anal. method has been effectively deployed for the screening and quantification of phenothiazine drugs in real-world samples sourced from com. livestock and aquatic products.