Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.

中文翻译：

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受辐照和化学疗法治疗的小鼠的神经系统损害。

放射疗法，外科手术和替莫唑胺（TMZ）是多形性胶质母细胞瘤（GBM）的一线治疗方法。尽管有益，GBM治疗仍然在近50％的患者中引起焦虑或抑郁。为了进一步了解这些神经系统并发症的基础，我们使用小鼠模型调查了放疗和TMZ化疗（联合治疗）联合治疗对神经功能缺损的影响。联合治疗五周后，小鼠表现出焦虑样行为，并且在15周时观察到焦虑和抑郁样行为。与血清素轴在情绪障碍中的已知作用有关，我们发现在早期和晚期时间点，海马中5HT1A血清素受体的水平均降低了约50％，照射后15周，血清素水平降低了37％。此外，用选择性5-羟色胺再摄取抑制剂氟西汀进行长期治疗足以逆转联合治疗引起的抑郁样行为。联合治疗还引起海马中激活的小胶质细胞短暂的早期增加，表明治疗诱导的神经炎症消退了15周。总之，这项研究的结果表明，针对血清素轴的干预措施可能有助于改善与GBM临床管理相关的某些神经系统副作用，从而改善癌症患者的整体生活质量。选择性5-羟色胺再摄取抑制剂氟西汀的长期治疗足以逆转联合治疗引起的抑郁样行为。联合治疗还引起海马中激活的小胶质细胞短暂的早期增加，表明治疗诱导的神经炎症消退了15周。总之，这项研究的结果表明，针对血清素轴的干预措施可能有助于改善与GBM临床管理相关的某些神经系统副作用，从而改善癌症患者的整体生活质量。选择性5-羟色胺再摄取抑制剂氟西汀的长期治疗足以逆转联合治疗引起的抑郁样行为。联合治疗还引起海马中激活的小胶质细胞短暂的早期增加，表明治疗诱导的神经炎症消退了15周。总之，这项研究的结果表明，针对血清素轴的干预措施可能有助于改善与GBM临床管理相关的某些神经系统副作用，从而改善癌症患者的整体生活质量。