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

Montay-Gruel, Pierre ; Acharya, Munjal M. ; Petersson, Kristoffer LU ; Alikhani, Leila ; Yakkala, Chakradhar ; Allen, Barrett D. ; Ollivier, Jonathan ; Petit, Benoit ; Jorge, Patrik Gonçalves and Syage, Amber R. , et al. (2019) In Proceedings of the National Academy of Sciences of the United States of America 166(22). p.10943-10951
Abstract

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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cognitive dysfunction, Neuroinflammation, Neuronal morphology, Reactive oxygen species, Ultra-high dose-rate irradiation
in
Proceedings of the National Academy of Sciences of the United States of America
volume
166
issue
22
pages
9 pages
publisher
National Academy of Sciences
external identifiers
  • pmid:31097580
  • scopus:85066269490
ISSN
0027-8424
DOI
10.1073/pnas.1901777116
language
English
LU publication?
no
additional info
Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.
id
c7e8224b-43aa-4cfa-8ffd-d984f2b2c7ff
date added to LUP
2021-11-03 18:17:53
date last changed
2024-04-20 15:45:00
@article{c7e8224b-43aa-4cfa-8ffd-d984f2b2c7ff,
  abstract     = {{<p>Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (&gt;100 Gy·s<sup>−1</sup>). Compared with conventional dose-rate (CONV; 0.07–0.1 Gy·s<sup>−1</sup>) 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.</p>}},
  author       = {{Montay-Gruel, Pierre and Acharya, Munjal M. and Petersson, Kristoffer and Alikhani, Leila and Yakkala, Chakradhar and Allen, Barrett D. and Ollivier, Jonathan and Petit, Benoit and Jorge, Patrik Gonçalves and Syage, Amber R. and Nguyen, Thuan A. and Baddour, Al Anoud D. and Lu, Celine and Singh, Paramvir and Moeckli, Raphael and Bochud, François and Germond, Jean François and Froidevaux, Pascal and Bailat, Claude and Bourhis, Jean and Vozenin, Marie Catherine and Limoli, Charles L.}},
  issn         = {{0027-8424}},
  keywords     = {{Cognitive dysfunction; Neuroinflammation; Neuronal morphology; Reactive oxygen species; Ultra-high dose-rate irradiation}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{22}},
  pages        = {{10943--10951}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species}},
  url          = {{http://dx.doi.org/10.1073/pnas.1901777116}},
  doi          = {{10.1073/pnas.1901777116}},
  volume       = {{166}},
  year         = {{2019}},
}