期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 22, 页码 10943-10951出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1901777116
关键词
ultra-high dose-rate irradiation; cognitive dysfunction; neuronal morphology; neuroinflammation; reactive oxygen species
资金
- Swiss National Fund (SNF) [31003A_156892]
- Fond'action
- SNF/French National Agency from Research [CR32I3L_156924]
- ISREC Foundation
- National Institute of Neurological Disorders and Stroke [NS089575]
- KL2 Award [KL2TR001416]
- Ecole Normale Superieure de Cachan Fellowship (Ministere de l'Enseignement Superieur et de la Recherche)
- Swiss National Science Foundation (SNF) [31003A_156892, CR32I3L_156924] Funding Source: Swiss National Science Foundation (SNF)
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.
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