Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway.
To investigate the neuroprotective role of sodium valproate (VPA) in a hippocampal neuronal cell line (HT22) and the hippocampus of zebrafish after exposure to radiation.



We investigated whether VPA could protect HT22 hippocampal neurons and the hippocampus of zebrafish from radiation-induced injury. We measured the generation of reactive oxygen species (ROS), the mitochondrial membrane potential, the levels of glutathione (GSH) and malondialdehyde (MDA), and the activity of superoxide dismutase (SOD). The expression of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was also measured. The cognitive behavior of the zebrafish was evaluated 1month after radiation exposure.



VPA treatment improved the survival rate (300 mg/kg body weight (BW) VPA: 76.67%; 100 mg/kg BW VPA: 56.7%) of zebrafish 1 month after exposure to a lethal dose of whole-body irradiation (P<0.01). VPA treatment decreased the ROS generation (P<0.01), decreased the MDA levels (P<0.01), increased the GSH levels (P<0.01) and increased the SOD activity (P<0.01). VPA treatment activated the Nrf2/HO-1 pathway, increased the nuclear translocation of Nrf2 and increased the mRNA (P<0.01) and protein expression of HO-1 to prevent radiation-induced neuronal injury. SiRNA knockdown of the Nrf2 gene prevented the VPA-induced attenuation of radiation injury in the HT22 neuronal cells that was found in the control cells (40.09±1.76% vs. 41.14±1.09%, P>0.05). VPA also improved the zebrafish cognitive behavior after radiation-induced neuronal injury as measured by the exploration test (control 5.74±1.42min vs. radiation therapy 16.39±4.03min vs. radiation therapy plus VPA 7.18±1.79min, P<0.05).



ROS generation after radiation exposure contributes to DNA damage in the zebrafish brain. VPA inhibits ROS generation by activating the Nrf2/HO-1 pathway, which improves cognitive behavior following radiation-induced neuronal injury.
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, China; Department of Radiation Oncology, Shenzhen people's Hospital, Second Clinical Medicine College of Jinan University, China; Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515 China.
Guixiang
G
Liao
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, China.
Rong
R
Li
Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515 China.
Xiaohui
X
Chen
Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515 China. Electronic address: wweismu2015@163.com.
Wenqing
W
Zhang
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, China. Electronic address: 23979463@qq.com.
Shasha
S
Du
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, China. Electronic address: yuanyawei2015@outlook.com.
Yawei
Y
Yuan
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003071:Cognition / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004353:Drug Evaluation, Preclinical; D029941:Fish Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D008565:Membrane Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014635:Valproic Acid / Q000494:pharmacology*; D015027:Zebrafish
D029941:Fish Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D014635:Valproic Acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
cognitive damage; ionizing irradiation; reactive oxygen species; sodium valproate