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Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species

2019; National Academy of Sciences; Volume: 116; Issue: 22 Linguagem: Inglês

10.1073/pnas.1901777116

1091-6490

Pierre Montay‐Gruel, Munjal M. Acharya, Kristoffer Petersson, Leila Alikhani, Chakradhar Yakkala, Barrett D. Allen, Jonathan Ollivier, Benoît Petit, Patrik Gonçalves Jorge, Amber R. Syage, Thuan A. Nguyen, Al Anoud D. Baddour, Celine Lu, Paramvir Singh, Raphaël Moeckli, François Bochud, Jean-François Germond, Pascal Froidevaux, Claude Bailat, Jean Bourhis, Marie‐Catherine Vozenin, Charles L. Limoli,

Nanoplatforms for cancer theranostics

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 neurocognitive 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 neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, 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.