Neuroprotective effects and mechanisms of ultra-high dose-rate FLASH radiotherapy against radiation-induced neural injury in mice
HE Renke
LIU Yuhan
XIE Shengqiang
LIU Jiayu
LI Wenxuan
CHENG Gang
ZHANG Jianning
Abstract：Objective To investigate the differences in neurological damage induced by ultra-high dose-rate FLASH radiotherapy(FLASH-RT)and conventional dose-rate radiotherapy(CONV-RT)in normal mice.Methods Thirty adult male C57BL/6J mice were randomly divided into Sham,CONV-RT,and FLASH-RT groups(n=10 per group).CONV-RT was delivered using a 6 MV Elekta linear accelerator,while FLASH-RT was administered via a 10 MV X-ray accelerator;both groups received a single 10 Gy whole-brain irradiation.Two months post-irradiation,cognitive function was assessed using the novel object recognition test and Y-maze test.Immunofluorescence staining was then performed to quantify microglia and astrocytes in the hippocampal region and cortical vascular density;laser speckle contrast imaging was used to analyze cerebral blood flow perfusion.Finally,proteomic analysis of brain tissue was conducted.Results Behavioral tests revealed that,two months after irradiation,mice in the CONV-RT group exhibited significant cognitive impairment in both the novel object recognition and Y-maze tests,whereas FLASH-RT markedly alleviated these behavioral deficits(P＜0.01).Immunofluorescence results indicated increased activation of microglia and astrocytes in the hippocampus and reduced cortical blood flow perfusion in the CONV-RT group.In contrast,the FLASH-RT group showed significantly attenuated neuroinflammation and improved cerebral blood flow perfusion(P＜0.05).GO enrichment analysis of proteomics suggested that CONV-RT primarily affected cell adhesion,synapse assembly,and metabolic processes,while FLASH-RT better preserved neural network structure and metabolic homeostasis.KEGG pathway analysis further demonstrated that FLASH-RT largely maintained synaptic and metabolic pathway functions and activated protective stress pathways such as AMPK,apoptosis,and HIF-1/VEGF.CONV-RT,however,led to widespread downregulation of neural,metabolic,and inflammation-related signaling.Conclusion Compared with CONV-RT,ultra-high dose-rate FLASH-RT effectively mitigates radiation-induced cognitive impairment,neuroinflammation,and cerebrovascular damage by maintaining neural connectivity,improving metabolic homeostasis,and activating protective stress pathways.
Keywords：radiotherapyradiation injuriesdose-response relationshipcognitive disordersneuroinflammationcerebrovascular circulationproteomicsmice
Publication Date：2026-02-28
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：8( 185-192 )