Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1–2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach.

Pexidartinib (PLX3397) 是一种集落刺激因子 1 受体 (CSF1R) 的小分子受体酪氨酸激酶抑制剂，与血小板衍生生长因子受体家族的其他成员相比具有中等选择性。它被批准用于治疗腱滑膜巨细胞瘤（TGCT）。CSF1R 在小胶质细胞中高度表达，小胶质细胞是中枢神经系统 (CNS) 的巨噬细胞，可保护 CNS 免受损伤和病原体的侵害，并有助于突触的发育和可塑性。受到病原体、凋亡细胞、碎片或炎症分子的挑战，它们采取响应状态来传播炎症并最终恢复到稳态。表型转换可能会失败，并且与疾病相关的小胶质细胞会导致神经退行性或神经精神疾病或脑、脊髓或神经损伤或缺血/出血后长期有害的脑炎症的病理生理学。小胶质细胞还有助于胶质母细胞瘤（GBM）生长的肿瘤微环境。在啮齿类动物中，通过pexidartinib食物颗粒连续治疗1-2周会导致小胶质细胞耗尽，随后剩余部分重新增殖，这得到了外周单核细胞寻找空位进行植入的帮助。这种小胶质细胞耗竭或强制更新的假定治疗益处已在几乎所有中枢神经系统疾病或损伤或 GBM 啮齿动物模型中进行了评估，结果具有异质性，但有部分有益效果的趋势。到目前为止，小胶质细胞监测（例如通过正电子发射成像）并不是接受 Pexidartinib（例如用于 TGCT）的患者的标准护理，因此人类的消耗和再增殖效率仍然在很大程度上未知。考虑到小胶质细胞的良性功能，持续耗竭可能不是治疗选择，但出现了短期短暂的部分耗竭，以刺激小胶质细胞更新或取代遗传性疾病中的小胶质细胞，并与干细胞移植等相结合或作为胶质母细胞瘤治疗中多模式概念的一部分可行的。本综述概述了支持和反对小胶质细胞消除作为治疗方法的临床前证据。