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In recent years, ultra-high dose rate (FLASH) radiotherapy has become one of the most advanced research topics in the field of radiotherapy. Experimental data indicate that FLASH radiotherapy can significantly reduce the irradiation damage in normal tissues while being as effective as clinical conventional dose rate radiotherapy in tumor control. The oxygen depletion hypothesis is considered as one of the key mechanisms underlying the FLASH effect. In this article, research progress on the discovery, experimental evidence and reaction principle of oxygen depletion was reviewed, the measurement methods and biological effect modeling methods of the oxygen depletion hypothesis were summarized, and the oxygen depletion difference between normal tissue and tumor was also discussed.
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Objective To evaluate the effects of neural stem cells (NSCs) overexpressing brainderived neurotrophic factor (BDNF) on the levels of neurotrophic factors and microglia activation in hippocampus after brain irradiation.Methods Hippocampal NSCs were isolated from fetal rat brain and infected with GFP-lentivirus and GFP-BDNF-lentivirus.SD rats were randomized into four groups:control group,irradiated group (R group),GFP-modified NSCs transplantation group with irradiation (R+NSCs group),and GFP-BDNF modified NSCs transplantation group with irradiation (R+BDNF-NSCs group).NSCs were transplanted into the bilateral hippocampus of rats one month after whole brain irradiation at a single dose of 20 Gy.The expressions of BDNF,glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in hippocampus were detected at 2 and 8 weeks after transplantation.The activation of microglia was observed by immunofluorescence.Results At 2 and 8 weeks after transplantation,the expressions of BDNF and NGF proteins in hippocampus of R+BDNF-NSCs group were significantly higher than those of R group (P＜0.05).The activated microglia in the R+NSCs group and the R+BDNF-NSCs group had no decrease compared with R group (P＞ 0.05).Conclusions The transplantation of NSCs overexpressing BDNF promotes the production of BDNF and NGF,which improves the level of neurotrophic factors in hippocampus after radiation.
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Objective@#To investigate the role of p75 neurotrophin receptor (p75NTR) in the irradiation-induced hippocampal neurogenesis impairment.@*Methods@#Thirty Sprague-Dawley rats were subject to whole brain irradiation with a single dose of 10 Gy 4 MeV electron beam. At 1 month after irradiation, the hippocampal tissues of the rats were collected. Western blot was used to detect the changes in the expression level of p75NTR protein. Immunofluorescence confocal laser microscopy was performed to observe the variations in the hippocampal neurogenesis. The stereotatic method was adopted for intra-hippocampal injection of AAV-shp75NTR to specifically knock out p75NTR.The relationship between p75NTR and hippocampal neurogenesis was analyzed.@*Results@#Western blot demonstrated that the expression of p75NTR protein was significantly up-regulated by 43.8% after irradiation (P<0.05). Immunofluorescent staining showed that the quantity of BrdU+ NeuN+ cells in rats was significantly decreased by 81.5% at 1 month after irradiation compared with that in the control group (P<0.01). After the specific knockout of p75NTR, hippocampal neurogenesis was obviously protected.@*Conclusion@#p75NTR plays a pivotal role in the irradiation-induced hippocampal neurogenesis impairment.
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Objective This study is to investigate the changes in the NFATc 4/3 signaling pathway in rat hippocampus after whole brain radiation. Methods A total of 120 one?month?old male Sprague?Dawley rats were randomly divided into four groups to receive whole brain radiation using 4?MeV electron beams with doses of 0( control) ,2,10,and 20 Gy,respectively,in a single fraction. At 6 hours,12 hours,1 day,3 days,1 week,and 2 weeks after radiation,Western blot and real?time PCR were used to evaluate the changes in expression levels of CaN, NFATc 4/3, p?NFATc 4/3, and GSK?3β. Results There were no significant changes in the expression of NFATc 4/3 or p?NFATc 4/3 at 6 and 12 hours after whole brain radiation. At 1 day after radiation,compared with the control group,the expression of p?NFATc 4/3 in the radiation groups was significantly increased in a dose?dependent manner ( 2 Gy:P= 0. 014;10 Gy:P=0. 011;20 Gy:P=0. 000 );however, there was no significant difference in the expression of NFATc 4/3 between the radiation group and the control group. The expression of NFATc 4/3 was significantly decreased in the radiation groups than in the control group at day 3 ( 2 Gy:P=0. 040;10 Gy:P=0. 000;20 Gy:P=0. 000),1 week (2 Gy:P=0. 692;10 Gy:P=0. 032;20 Gy:P=0. 021),and 2 weeks (2 Gy:P=0. 001;10 Gy:P=0. 000;20 Gy:P=0. 000) after radiation,while there was no significant difference in the expression of p?NFATc 4/3 between any two groups. There were no time?or dose?dependent changes in expression of CaN or GSK?3β. Conclusions Ionization radiation has an inhibitory effect on the NFATc 4/3 signaling pathway in rat hippocampus. Combined with our previous results,this study suggests that radiation?induced cognitive dysfunction is associated with the NFATc 4/3 signaling pathway.
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Objective To explore the effects of various radiation doses on the NFAT3/c4 signaling pathway and the improvement effect of exogenous brain-derived neurotrophic factor(BDNF)on this pathway. Methods Four groups of one-month-old Sprague-Dawley rats received radiation doses of 0,2,10,and 20 Gy, respectively, in a single radiation. At three days after radiation, exogenous BDNF was injected stereotaxically into the bilateral hippocampus. Western blotting and RT-PCR were used to assess the levels of NFAT3/c4-related proteins in the hippocampus. Results The results of Western blotting and RT-PCR showed that the level of NFAT3/c4 was reduced in a dose-and time-dependent manner after ionizing radiation. Compared with the radiation alone group,the ionizing radiation plus BDNF group had significantly increased levels of NFAT3/c4 and CaN with increases in radiation dose and time. Conclusions Whole brain radiotherapy inhibits the CaN/NFAT3/c4 signaling pathway. Exogenous BDNF can promote the NFAT-dependent transcription and then improve the cognitive function.
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Objective To investigate the effects of low dose radiation on dendritic growth of newborn neurons in the hippocampus of young rat.Methods One month-old male rats were randomized into radiation group aind sham control group.Radiation group received whole brain irradiation at a single dose of 2 Gy.Retrovirus expressing green fluorescent protein (GFP) was used to label newborn neurons in the hippocampus through stereotaxic intracranial infusion.Immunofluorescence assays were performed to detect dendritic architecture alterations induced by irradiation at different time points.Results Compared with control group,the lengths of total dendrite and the longest dendrite significantly decreased at 2 and 4 weeks after irradiation (t =3.10,2.07,2.94,4.02,P ＜ 0.05).The branching points of new born neurons were also decreased significantly at 2 weeks post irradiation (t =2.23,P ＜ 0.05).The number of new born neurons reduced at 4 weeks post irradiation (t =8.43,P ＜ 0.05).Conclusions Low dose radiation could inhibit newborn neuron growth in the hippocampus of young rat,which may be one of the most important mechanisms involved in radiation-induced cognitive impairment.