PLX5622 is a selective inhibitor of colony-stimulating factor 1 receptor (CSFR1) with an IC50 value of 0.016μM[1]. PLX5622 mainly acts on microglia in the central nervous system[2].[2]. By inhibiting CSFR1, PLX5662 selectively depletes microglia without affecting other types of myeloid cells[2]. PLX5662 has been investigated as a tool to study the role of microglia in neurodegenerative diseases[2].
In vitro, primary mixed mouse astrocytes and microglia cells were extracted[3]. Cells were treated with 10 μM PLX5622 (Dilute with 20mM DMSO stock solution), where other control cells were treated with DMSO only[3]. After treating microglial cells with 10μM PLX5622, cell number starting im-mediately after cell extraction was reduced to 8% of the control group, and cell number starting at day in vitro 12 was further reduced to 25% of the control group[3]. After 4 weeks treatment, number of microglial decreased to 2%, then dropped to less than 0.5% after 6 weeks[3]. PLX5622 significantly inhibited the growth of microglia.
In vivo, C57BL/6NCrl mice were fed a diet with PLX5622 at 1200 mg/kg, while control groups were fed a diet with AIN76 at the same concentration[4]. After 5 months, a 95% reduction of microglia was observed in mice[4]. Resident macrophages in multiple organs were depleted, including colon (92.4%); adipose tissue (58.2%); lung (26.3%) and peritoneal cavity (90.2%)[4]. However, a recovery of microglia has been observed after removal of PLX5622[4]. The same repopulation was also shown in bone marrow and spleen, indicating that immune cells could revert after withdrawal of PLX5622[4].
References:
[1]Guenoun D, Blaise N, Sellam A, Roupret‐Serzec J, Jacquens A, Steenwinckel JV, Gressens P, Bokobza C. Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF‐1R. Glia. 2024 Dec 24.
[2]Spangenberg E, Severson PL, Hohsfield LA, Crapser J, Zhang J, Burton EA, Zhang Y, Spevak W, Lin J, Phan NY, Habets G. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nature communications. 2019 Aug 21;10(1):3758.
[3]Hupp S, Iliev AI. CSF-1 receptor inhibition as a highly effective tool for depletion of microglia in mixed glial cultures. Journal of neuroscience methods. 2020 Feb 15;332:108537.
[4]Bosch AJ, Keller L, Steiger L, Rohm TV, Wiedemann SJ, Low AJ, Stawiski M, Rachid L, Roux J, Konrad D, Wueest S. CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice. Diabetologia. 2023 Dec;66(12):2292-306.
PLX5622是一种集落刺激因子1受体（CSFR1）的选择性抑制剂，IC50值为0.016μM[1]。PLX5662主要作用于中枢神经系统中的小胶质细胞[2]。通过抑制 CSFR1受体，PLX5662 选择性地清除小胶质细胞，而不影响其他类型的骨髓细胞[2]。PLX5662是研究小胶质细胞在神经退行性疾病中作用的工具[2]。
在体外，提取原代混合小鼠星形胶质细胞和小胶质细胞[3]。细胞用10 μM PLX5622（用20 mM DMSO母液液稀释）处理，其他对照细胞仅用DMSO处理[3]。用10 μM PLX5622处理小胶质细胞后，从细胞提取后立即开始的细胞数量减少到对照组的8%，而从体外培养第12天开始的细胞数量则只减少到对照组的25%[3]。4 周后，小胶质细胞数量下降至 2%，6周后下降至不足0.5%[3]。PLX5622显著抑制了小胶质细胞的生长。
在体内，C57BL/6NCrl小鼠饲喂剂量1200mg/kg的PLX5622饮食，而对照组饲喂相同浓度的AIN76饮食[4]。5个月后，观察到小鼠的小胶质细胞减少了95%[4]。多个器官中的常驻巨噬细胞被耗尽，包括结肠（92.4%）；脂肪组织（58.2%）；肺（26.3%）和腹膜腔（90.2%）[4]。然而，在去除PLX5622后观察到小胶质细胞的恢复[4]。骨髓和脾脏中也显示出相同的重新增殖，表明免疫细胞在停止PLX5622后可以恢复[4]。