Abstract

Background

Normal tissue toxicity is an inevitable consequence of primary or secondary brain tumor radiotherapy. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuroinflammation, and demyelination are contributing factors that lead to progressive cognitive decline.

Methods

The effects of 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) on irradiated murine neurospheres, microglia cells, and patient-derived gliomaspheres were assessed by sphere-formation assays, flow cytometry, and interleukin (IL)-6 enzyme-linked immunosorbent assay. Activation of the hedgehog pathway was studied by quantitative reverse transcription PCR. The in vivo effects of NSPP were analyzed using flow cytometry, sphere-formation assays, immunohistochemistry, behavioral testing, and an intracranial mouse model of glioblastoma.

Results

We report that NSPP mitigates radiation-induced normal tissue toxicity in the brains of mice. NSPP treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, and inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine IL-6. Behavioral testing revealed that treatment with NSPP after radiotherapy was able to successfully mitigate radiation-induced decline in memory function of the brain. In mouse models of glioblastoma, NSPP showed no toxicity and did not interfere with the growth-delaying effects of radiation.

Conclusions

We conclude that NSPP has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the central nervous system warrants further investigation.

中文翻译：

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脑辐照后 1-[(4-硝基苯基)磺酰基]-4-苯基哌嗪治疗可保留小鼠的认知功能。

摘要

背景

正常组织毒性是原发性或继发性脑肿瘤放疗的必然结果。颅脑照射通常会导致神经认知缺陷，这些缺陷会在治疗后数月或数年出现。从机制上讲，辐射诱导的神经干/祖细胞丢失、神经炎症和脱髓鞘是导致进行性认知衰退的因素。

方法

1-[(4-硝基苯基)磺酰基]-4-苯基哌嗪 (NSPP) 对辐照的小鼠神经球、小胶质细胞和患者来源的胶质瘤的影响通过球形成测定、流式细胞术和白细胞介素 (IL)- 6 酶联免疫吸附试验。通过定量逆转录PCR研究hedgehog途径的激活。使用流式细胞术、球体形成测定、免疫组织化学、行为测试和脑胶质母细胞瘤小鼠模型分析 NSPP 的体内效应。

结果

我们报告说，NSPP 减轻了小鼠大脑中辐射引起的正常组织毒性。NSPP 治疗显着增加了雌性动物脑照射后神经干/祖细胞的数量，并抑制了辐射诱导的小胶质细胞活化和促炎细胞因子 IL-6 的表达。行为测试表明，放射治疗后使用 NSPP 治疗能够成功缓解辐射引起的大脑记忆功能下降。在胶质母细胞瘤的小鼠模型中，NSPP 没有表现出毒性，也不会干扰辐射的生长延迟效应。

结论

我们得出结论，NSPP 有可能在不促进肿瘤生长的情况下减轻接受部分或全脑照射的患者的认知能力下降，并且使用这种化合物作为辐射缓解剂对中枢神经系统的辐射迟发效应值得进一步研究。