Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments
Attenuation of neuroinflammation reverses Adriamycin-induced cognitive impairments
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DOI：
10.1186/s40478-019-0838-8
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发表时间：
2019-11-21
影响因子：
7.1
通讯作者：
Acharya, Munjal M.
中科院分区：
文献类型：
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作者：
Allen, Barrett D.;Apodaca, Lauren A.;Acharya, Munjal M.
许多临床研究已经证实，化疗在治疗乳腺癌（通常被称为化疗脑）时，会导致神经认知功能衰弱。我们假设认知障碍与大脑中升高的小胶质细胞炎症有关。因此，无论是消除小胶质细胞还是恢复小胶质细胞功能都可以改善认知功能障碍。采用一种常用的乳腺癌化疗药物慢性阿霉素（ADR）治疗的啮齿动物模型，我们评估了两种改善化学脑的策略：1)使用集落刺激因子-1受体（CSF1R）抑制剂PLX5622去除小胶质细胞，2)人类诱导多能干细胞衍生的小胶质细胞（iMG）衍生的细胞外囊泡（EV）治疗。在策略1中，小鼠每周接受一次ADR，持续4周，然后在ADR治疗后72小时开始给予CSF1R抑制剂（PLX5622）。4-6周后，给予正常饮食的药物不良反应治疗的动物表现出明显的行为缺陷和增加的小胶质细胞激活。plx5622处理的小鼠没有表现出与adr相关的认知缺陷，并且大脑中IBA-1和CD68（+）小胶质细胞几乎完全耗尽。炎症通路的细胞因子和RNA测序分析证实了这些发现。在策略2中，在最后一次ADR治疗后1周，小鼠接受眼眶后静脉注射iMG-EV（每周一次，持续4周），1周后，小鼠进行行为测试。与未治疗的ADR小鼠相比，接受EV治疗的ADR小鼠的认知功能几乎完全恢复，小胶质细胞激活显著减少。我们的数据表明，不良反应治疗会增加与认知功能障碍相关的中枢神经系统炎症，而神经炎症的减弱逆转了化疗的不良神经认知效应。
Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68(+) microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy.