Journal article
Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy
Neuro-oncology (Charlottesville, Va.), Vol.25(5), pp.927-939
05/2023
DOI: 10.1093/neuonc/noac248
PMCID: PMC10158064
PMID: 36334265
Abstract
BACKGROUNDUltra-high dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising anti-tumor efficacy compared to conventional dose rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. METHODSCohorts of three-week-old male and female C57Bl/6 mice exposed to hypofractionated (2×10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months post-treatment. Animals were sacrificed 6 months post-irradiation and tissues analyzed for neurological and cerebrovascular decrements. RESULTSThe neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin) and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and a preservation of cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. CONCLUSIONSHypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlight its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.
Details
- Title: Subtitle
- Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy
- Creators
- Barrett D Allen - University of California, IrvineYasaman Alaghband - University of California, IrvineEniko A Kramár - University of California, IrvineNing Ru - University of California, IrvineBenoit Petit - University of LausanneVeljko Grilj - University of LausanneMichael S Petronek - University of IowaCasey F Pulliam - University of IowaRachel Y Kim - University of California, IrvineNgoc-Lien Doan - University of California, IrvineJanet E Baulch - University of California, IrvineMarcelo A Wood - University of California, IrvineClaude Bailat - University of LausanneDouglas R Spitz - University of IowaMarie-Catherine Vozenin - University of LausanneCharles L Limoli - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Neuro-oncology (Charlottesville, Va.), Vol.25(5), pp.927-939
- DOI
- 10.1093/neuonc/noac248
- PMID
- 36334265
- PMCID
- PMC10158064
- NLM abbreviation
- Neuro Oncol
- eISSN
- 1523-5866
- Grant note
- name: Spirit grant MC-V, award: P01CA244091, R01CA2544892; name: Optical Biology Core Facility of the Developmental Biology Center, award: CA-62203; DOI: 10.13039/100019092, name: Center for Complex Biological Systems, award: GM-076516; DOI: 10.13039/100008476, name: University of California, Irvine
- Language
- English
- Electronic publication date
- 11/05/2022
- Date published
- 05/2023
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984314279302771
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