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小 猫 说 随着医疗技术和条件的进步，癌症生存率相较于之前有较高的提升，但癌症治疗过程中经化疗手段治疗的患者有超过一半存在化疗导致的认知障碍，这种症状可能存在一定时间，给患者生活带来不便。发表于《Cell》的本研究中，科学家致力于寻找能够提高癌症幸存者生活质量的治疗方法，以治疗癌症患者的“化疗脑”。本研究通过研究化疗药物甲氨蝶呤对神经系统的影响，发现了化疗导致认知障碍的治疗靶点。 Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment  图片来源：文献原文 Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. 甲氨蝶呤化疗诱导持续性三神经胶质细胞失调是化疗相关认知障碍的基础 化疗会导致一种常见的长期神经功能缺损综合症，但人们对此知之甚少。神经前体细胞功能障碍和白质功能障碍被认为是造成这种衰弱综合征的原因。我们证明了接受化疗的人体中少突胶质细胞的持续消耗。通过建立甲氨蝶呤化疗诱导的神经功能障碍的小鼠模型，我们发现相似的白质OPCs消耗：OPC分化增加但不完全，髓鞘形成持续缺乏。初次接受化疗的小鼠OPCs在移植到先前暴露于甲氨蝶呤的大脑微环境后，表现出更高的分化，表明潜在的微环境干扰。甲氨蝶呤导致小胶质细胞的持续活化及随后星形细胞的活化——其依赖于炎性小胶质细胞。小胶质细胞的消耗使甲氨蝶呤化疗后的少突胶质细胞谱系动力学、髓鞘微观结构和认知行为正常化。这些研究结果表明，暴露于甲氨蝶呤化疗与三神经胶质的持续失调有关，并确定了炎性小胶质细胞可作为消除化疗相关认知障碍的治疗靶点。 文献来源 Gibson, E. M., et al. (2018). Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell, 176(1):p43-55.E13. Doi:10.1016/j.cell.2018.10.049. 备注：浦美医学每周推出一个专题的“文献速递”汇编，如需详细了解内容或全文请联系我们（浦美小编：微信号pumeixiaobian）。文献内容均由浦美医学编译自原文，疏漏之处敬请读者指正。 |
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