title: Irradiation-induced hippocampal neurogenesis impairment is associated with epigenetic regulation of bdnf gene transcription.
abstract: Radiotherapy is often employed for the treatment of head and neck cancer. Unfortunately, its neurotoxic effects on normal brain tissue often compromise the quality of life (QOL) for survivors. Particularly, acute cognitive deficit (ACD), which can occur several days to one month after irradiation, limits its therapeutic use. Impairment of neurogenesis in the hippocampus plays a key role in the development of radiation-induced cognitive deficit, and brain-derived neurotrophic factor (BDNF) may be involved. In the present study, we re-evaluated the effects of different doses of radiation on the development of ACD in Sprague Dawley rats. Our results showed that 30 Gy, but not 2 Gy or 10 Gy of whole brain radiation (WBI), led to significant deficits in cognitive functions at one month post-irradiation. At 7 and 30 days post-irradiation, immunofluorescence showed WBI had seriously impeded the production of new neurons and shortened their survival time. Additionally, decreased bdnf mRNA and protein expression were also observed. A significant decrease in histone deacetylase 1 (HDAC1)-dependent H3 acetylation was observed at bdnf promoters by ChIP analysis. TSA, an HDAC inhibitor, triggered bdnf transcription and rescued neurogenesis impairment following WBI. In summary, our results suggest that a single-dose exposure to 30 Gy WBI induced acute cognitive dysfunction in rats. Additionally, radiation-induced persistent inhibition of bdnf gene transcription resulting from lowered rates of HDAC1-dependent H3 acetylation was associated with long-term impairment of neurogenesis in the denate gyrus (DG). Triggering of BDNF-TrkB signaling by inhibition of HDAC-1 may be used to stimulate neurogenesis.
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China. Electronic address: dryetian@hotmail.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: The Institute of Neuroscience, Zhejiang University, Yuhangtang Road No. 866, Hangzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Institute of Neuroscience, Zhejiang University, Yuhangtang Road No. 866, Hangzhou, Zhejiang, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000528:radiation effects; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000503:physiopathology* / Q000528:radiation effects*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D008297:Male; D058953:Neural Stem Cells / Q000502:physiology / Q000528:radiation effects; D055495:Neurogenesis / Q000235:genetics / Q000528:radiation effects*; D009474:Neurons / Q000502:physiology / Q000528:radiation effects; D011401:Promoter Regions, Genetic / Q000528:radiation effects; D046188:Protein Modification, Translational / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020813:Receptor, trkB; C515890:Hdac1 protein, rat; D056284:Histone Deacetylase 1
keywords: HDAC1; Histone acetylation; Neurogenesis; Whole brain irradiation; bdnf