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

IF 5.4 2区 医学 Q1 NEUROSCIENCES
Glia Pub Date : 2025-02-01 Epub Date: 2024-11-04 DOI:10.1002/glia.24637
Noelia Rodriguez-Iglesias, Iñaki Paris, Jorge Valero, Lorena Cañas-Zabala, Alejandro Carretero, Klas Hatje, Jitao David Zhang, Christoph Patsch, Markus Britschgi, Simon Gutbier, Amanda Sierra
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引用次数: 0

Abstract

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.

一种自下而上的方法确定了抗精神病和抗肿瘤药物三氟拉嗪以及核糖衍生物脱氧小檗碱为新型小胶质细胞吞噬抑制剂。
吞噬是大脑专业吞噬细胞--小胶质细胞不可或缺的功能。在生理条件下,小胶质细胞尤其能高效吞噬发生程序性细胞死亡(凋亡)的细胞。然而,越来越多的证据表明,在多种脑部疾病中,小胶质细胞的吞噬功能存在障碍。这些观察结果促使我们寻找具有治疗潜力的吞噬调节剂(增强剂或抑制剂)。我们采用了自下而上的策略,包括在细胞培养中使用表型高通量筛选(HTS)鉴定吞噬调节剂,并在器官型培养物和体内进行验证。我们进行了两个互补的 HTS 试验:在 Achucarro,我们使用了小鼠小胶质细胞的原代培养物和 Prestwick 化学文库中的化合物;在罗氏,我们使用了人 iPSC 衍生的巨噬细胞样细胞和包含 2200 种已知作用机制化合物的专有化学基因组文库。接下来,我们利用海马器官型培养物验证了更强效的化合物,并确定了两种吞噬抑制剂:三氟哌嗪(一种多巴胺能和肾上腺素能拮抗剂,用作抗精神病药和抗肿瘤药)和脱氧小檗碱(一种核糖衍生物)。最后,我们通过使用渗透性微型泵将这些化合物注入小鼠海马,测试它们是否能够调节体内成年海马神经源龛中新生细胞凋亡的吞噬作用。我们证实三氟拉嗪和脱氧小檗碱都具有体内抗吞噬活性,并验证了我们自下而上识别新型吞噬调节剂的策略。这些结果表明,在药物发现项目中,注释了作用机制的化学库是对小胶质细胞进行药理调节的起点,其目的是对脑部疾病中的吞噬作用进行治疗操纵。
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来源期刊
Glia
Glia 医学-神经科学
CiteScore
13.10
自引率
4.80%
发文量
162
审稿时长
3-8 weeks
期刊介绍: GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.
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