Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation
Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation
复制标题
DOI：
10.1016/j.radonc.2019.06.006
复制
发表时间：
2019-10-01
影响因子：
5.7
通讯作者：
Loo, Billy W., Jr.
中科院分区：
文献类型：
--
作者：
Simmons, Danielle A.;Lartey, Frederick M.;Loo, Billy W., Jr.
目的：探讨超快速闪光照射对C57BL6/J小鼠脑照射后认知功能障碍相关因素--海马树突棘和神经炎症的影响。方法：采用自制临床直线加速器，对C57BL6/J小鼠进行30Gy亚秒级闪光全脑照射，与常规照射时间240GyBL6/J小鼠进行比较。照射后10周，我们使用新的物体定位和物体识别测试来评估空间和非空间物体识别。我们通过追踪高尔基染色的海马神经元来测量树突棘密度，并通过CD68免疫染色(激活的小胶质细胞的标志)和10种促炎细胞因子的多重免疫分析来评估神经炎症。结果：在照射后10周，与未照射的对照组相比，常规投放时间照射显著损害了新物体的定位和识别任务，而相同剂量的闪光投射没有显著影响。传统的分娩时间，而不是闪光，与海马顶端树突中树突棘密度的显著损失有关，在基底树突中也有类似的非显著趋势。与对照组相比，常规分娩时间与CD68阳性小胶质细胞显着增加相关，而闪光不相关。常规给药时间与海马区10个促炎细胞因子中有5个显著增加(另3个无明显增加)，而闪光照射仅与3个较小的增加有关。结论：与常规给药时间照射相比，闪光照射可减少认知功能障碍和相关的神经变性，可能是通过减少神经炎症的诱导，为提高脑肿瘤放射治疗的治疗指数提供了一种有前景的方法。(C)2019爱思唯尔B.V.保留所有权利。
Aim: To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation.Methods: We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay.Results: At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3.Conclusion: Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors. (C) 2019 Elsevier B.V. All rights reserved.