Cancer treatment induces neuroinflammation and behavioral deficits in mice.
Cancer treatment induces neuroinflammation and behavioral deficits in mice.
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DOI：
10.3389/fnbeh.2022.1067298
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发表时间：
2022
影响因子：
3
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中科院分区：
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简介：越来越多的癌症幸存者被诊断出患有称为癌症相关认知障碍（CRCI）的神经认知功能障碍综合征。化疗和放疗与CRCI有关;然而，其潜在的发病机制仍不清楚，阻碍了有效的预防或治疗。研究方法：我们使用无毛品系SKH 1（11-12周龄），并对小鼠右后肢进行放射治疗，阿霉素（化疗剂），同时进行放射治疗和阿霉素，或不进行治疗（对照）。治疗后通过标准化行为测试评估神经认知。随后对小鼠实施人道安乐死，并收集血浆和脑以鉴定炎症变化。结果如下：与对照小鼠相比，用辐射、多柔比星或辐射和多柔比星两者处理的小鼠表现出等同的海马依赖性记忆缺陷和活化的小胶质细胞和星形胶质细胞的显著增加。在研究期间，与对照小鼠相比，多柔比星治疗小鼠的血浆IL-6显著增加，并且体重没有增加。讨论：本研究表明，非脑定向辐射诱导神经胶质增生和神经认知缺陷。此外，这项工作首次将SKH 1小鼠表征为CRCI的相关和简单的动物模型。这项研究提供了一个平台，从中可以建立进一步的研究，以确定有助于CRCI的潜在关键靶点，从而可以制定策略来减轻与抗癌治疗相关的非预期神经病理学后果。
Introduction: Cancer survivors are increasingly diagnosed with a syndrome of neurocognitive dysfunction termed cancer-related cognitive impairment (CRCI). Chemotherapy and radiation therapy have been implicated in CRCI; however, its underlying pathogenesis remains unclear, hindering effective prevention or treatment. Methods: We used the hairless strain SKH1 (11–12-week-old) and treated the mice with radiation to the right hindlimb, doxorubicin (a chemotherapy agent), concurrent radiation, and doxorubicin, or no treatment (control). Neurocognition was evaluated via standardized behavioral testing following treatment. Mice were subsequently humanely euthanized, and plasma and brains were collected to identify inflammatory changes. Results: Mice treated with radiation, doxorubicin, or both radiation and doxorubicin demonstrated equivalent hippocampal dependent memory deficits and significant increases in activated microglia and astrocytes compared to control mice. Doxorubicin-treated mice had significantly increased plasma IL-6 and failed to gain weight compared to control mice over the study period. Discussion: This study demonstrates that non-brain directed radiation induces both gliosis and neurocognitive deficits. Moreover, this work presents the first characterization of SKH1 mice as a relevant and facile animal model of CRCI. This study provides a platform from which to build further studies to identify potential key targets that contribute to CRCI such that strategies can be developed to mitigate unintended neuropathologic consequences associated with anticancer treatment.