PMID- 28992110
OWN - NLM
STAT- MEDLINE
DCOM- 20180723
LR  - 20200111
IS  - 1349-9157 (Electronic)
IS  - 0449-3060 (Print)
IS  - 0449-3060 (Linking)
VI  - 58
IP  - 6
DP  - 2017 Nov 1
TI  - NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during 
      radiation-induced brain injury.
PG  - 827-833
LID - 10.1093/jrr/rrx041 [doi]
AB  - Whole brain irradiation (WBI) has become an indispensible tool in the treatment 
      of head and neck cancer, and it has greatly improved patient survival rate and 
      total survival time. In addition, prophylactic cranial irradiation (PCI) has 
      dramatically decreased the incidence of brain metastatic carcinoma. However, WBI 
      may induce temporary functional deficits or even progressive, irreversible 
      cognitive dysfunction that compromises the quality of life for survivors. 
      Unfortunately, the exact molecular mechanisms for cognitive damage remain 
      elusive, and no treatment or preventative measures are available for use in the 
      clinic. In the present study, the nuclear factor of activated T cells isoform 4 
      (NFAT3/c4) was found to play a vital role in excitotoxic hippocampus cell 
      apoptosis induced by radiation. Sprague-Dawley (SD) rats received 20 Gy WBI, 
      after which we detected NFAT3/c4-mediated excitotoxicity. We found that radiation 
      caused hippocampus excitotoxicity, resulting from overactivation of the 
      N-methyl-D-aspartate receptor (NMDAR) and always accompanied by subsequent 
      elevation of the intracellular calcium level and activation of calcineurin (CaN). 
      P-NFAT3/c4 was the principal downstream target of CaN, including regulation of 
      its nuclear translocation as well as transcriptional activities. Radiation 
      recruited NMDAR/NFAT3/c4 activation and subsequent Bax induction in hippocampus 
      cells. Once treated with the NFAT3/c4 inhibitor 11R-VIVIT peptide 
      pre-irradiation, hippocampal proliferation and neuron survival (dentate gyrus 
      cells in particular) were protected from radiation-induced injury, resulting in 
      inhibition of the apoptosis marker Bax. Our principal aim was to illuminate the 
      role of NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during 
      radiation-induced brain injury. This study is the first time that 
      radiation-induced activation of NFAT3/c4 has been recorded, and our results 
      suggest that NFAT3/c4 may be a novel target for prevention and treatment of 
      radiation-induced brain injury.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of The Japan 
      Radiation Research Society and Japanese Society for Radiation Oncology.
FAU - Xu, Meiling
AU  - Xu M
AD  - Department of Radiotherapy and Oncology, The Second Affiliated Hospital of 
      Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
FAU - Fan, Qiuhong
AU  - Fan Q
AD  - Institute of Radiotherapy & Oncology, Soochow University.
FAU - Zhang, Junjun
AU  - Zhang J
AD  - Suzhou Key Laboratory for Radiation Oncology, San Xiang Road No. 1055, Suzhou 
      215004, China.
FAU - Chen, Yanfang
AU  - Chen Y
AD  - Department of Radiotherapy and Oncology, The Second Affiliated Hospital of 
      Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
FAU - Xu, Ruizhe
AU  - Xu R
AD  - Institute of Radiotherapy & Oncology, Soochow University.
FAU - Chen, Liesong
AU  - Chen L
AD  - Department of Radiotherapy and Oncology, The Second Affiliated Hospital of 
      Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
FAU - Zhao, Peifeng
AU  - Zhao P
AD  - Department of Radiotherapy and Oncology, The Second Affiliated Hospital of 
      Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
FAU - Tian, Ye
AU  - Tian Y
AD  - Department of Radiotherapy and Oncology, The Second Affiliated Hospital of 
      Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004, China.
LA  - eng
PT  - Journal Article
PL  - England
TA  - J Radiat Res
JT  - Journal of radiation research
JID - 0376611
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Neurotoxins)
RN  - 0 (Oligopeptides)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (VIVIT peptide)
RN  - 0 (bcl-2-Associated X Protein)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Body Weight
MH  - Brain Injuries/complications/*metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Cognition Disorders/complications/pathology
MH  - Cranial Irradiation
MH  - Dentate Gyrus/pathology
MH  - Hippocampus/*pathology
MH  - Male
MH  - NFATC Transcription Factors/*metabolism
MH  - Neurons/drug effects/pathology
MH  - Neurotoxins/*toxicity
MH  - Oligopeptides/pharmacology
MH  - Organ Size
MH  - Radiation Injuries/complications/*metabolism/pathology
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Signal Transduction/drug effects
MH  - bcl-2-Associated X Protein/metabolism
PMC - PMC5710526
OTO - NOTNLM
OT  - Bax
OT  - NFAT3/c4
OT  - NMDAR
OT  - apoptosis
OT  - calcineurin
OT  - radiation
EDAT- 2017/10/11 06:00
MHDA- 2018/07/24 06:00
PMCR- 2017/08/10
CRDT- 2017/10/10 06:00
PHST- 2017/03/01 00:00 [received]
PHST- 2017/10/11 06:00 [pubmed]
PHST- 2018/07/24 06:00 [medline]
PHST- 2017/10/10 06:00 [entrez]
PHST- 2017/08/10 00:00 [pmc-release]
AID - 4080277 [pii]
AID - rrx041 [pii]
AID - 10.1093/jrr/rrx041 [doi]
PST - ppublish
SO  - J Radiat Res. 2017 Nov 1;58(6):827-833. doi: 10.1093/jrr/rrx041.