Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species
Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species
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DOI：
10.1073/pnas.1901777116
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发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Limoli, Charles L.
中科院分区：
文献类型：
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作者：
Montay-Gruel, Pierre;Acharya, Munjal M.;Limoli, Charles L.
在这里，我们强调使用超高剂量率(>；100Gy.s(-1))提供闪光放射治疗的潜在转换好处。与传统剂量率(Conv；0.07-0.1Gy.s(-1))模式相比，我们发现闪光不会导致辐射诱导的小鼠学习和记忆障碍。此外，暴露6个月后，Conv导致神经认知终点发生永久性变化，而闪光不会导致焦虑和抑郁的行为，也不会损害消亡记忆。机制研究表明，通过二氧化碳呼吸提高大脑中的氧分压，逆转了闪光的神经保护作用，而放射化学研究证实，闪光产生的有毒活性氧种过氧化氢水平较低。此外，闪光不会诱发神经炎症，这一过程被描述为氧化应激依赖，也与显著保存神经元形态和树突棘密度有关。闪光提供的非凡的正常组织保存有朝一日可能会为肿瘤床上的剂量升级提供迄今尚未实现的机会，这些能力有望加速将这一突破性的放射方式转化为临床实践。
Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy.s(-1)). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy.s(-1)) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neuro-cognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuro-protective effects of FLASH, while radio chemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuro-inflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.