丙戊酸钠通过激活Nrf2/HO-1通路预防辐射诱导的海马神经元损伤。
Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway.
作者信息
Liao Guixiang, Li Rong, Chen Xiaohui, Zhang Wenqing, Du Shasha, Yuan Yawei
机构信息
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.
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, China.
出版信息
Neuroscience. 2016 Sep 7;331:40-51. doi: 10.1016/j.neuroscience.2016.06.019. Epub 2016 Jun 17.
PURPOSE
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
目的
研究丙戊酸钠（VPA）在辐射暴露后对海马神经元细胞系（HT22）和斑马鱼海马体的神经保护作用。
方法
我们研究了VPA是否能保护HT22海马神经元和斑马鱼海马体免受辐射诱导的损伤。我们测量了活性氧（ROS）的产生、线粒体膜电位、谷胱甘肽（GSH）和丙二醛（MDA）的水平以及超氧化物歧化酶（SOD）的活性。还测量了核因子（红细胞衍生2）相关因子2（Nrf2）和血红素加氧酶-1（HO-1）的表达。在辐射暴露1个月后评估斑马鱼的认知行为。
结果
VPA处理提高了斑马鱼在接受致死剂量全身照射1个月后的存活率（300mg/kg体重（BW）VPA：76.67%；100mg/kg BW VPA：56.7%）（P<0.01）。VPA处理降低了ROS的产生（P<0.01），降低了MDA水平（P<0.01），增加了GSH水平（P<0.01）并增加了SOD活性（P<0.01）。VPA处理激活了Nrf2/HO-1途径，增加了Nrf2的核转位并增加了HO-1的mRNA（P<0.01）和蛋白表达，以预防辐射诱导的神经元损伤。Nrf2基因的小干扰RNA敲低阻止了VPA诱导的HT22神经元细胞中辐射损伤的减轻，而在对照细胞中观察到这种减轻（40.09±1.76%对41.14±1.09%，P>0.05）。通过探索试验测量，VPA还改善了辐射诱导神经元损伤后斑马鱼的认知行为（对照5.74±1.42分钟对放疗16.39±4.03分钟对放疗加VPA 7.18±1.79分钟，P<0.05）。
结论
辐射暴露后ROS的产生导致斑马鱼大脑中的DNA损伤。VPA通过激活Nrf2/HO-1途径抑制ROS的产生，从而改善辐射诱导神经元损伤后的认知行为。
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