SODIUM VALPROATE PREVENTS RADIATION-INDUCED INJURY IN HIPPOCAMPAL NEURONS VIA ACTIVATION OF THE Nrf2/HO-1 PATHWAY
SODIUM VALPROATE PREVENTS RADIATION-INDUCED INJURY IN HIPPOCAMPAL NEURONS VIA ACTIVATION OF THE Nrf2/HO-1 PATHWAY
复制标题
丙戊酸钠通过激活 Nrf2/HO-1 通路预防海马神经元辐射引起的损伤
DOI：
10.1016/j.neuroscience.2016.06.019
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发表时间：
2016-09-07
期刊：
影响因子：
3.3
通讯作者：
Yuan, Yawei
中科院分区：
文献类型：
--
作者：
Liao, Guixiang;Li, Rong;Yuan, Yawei
目的：研究丙戊酸钠（VPA）对海马神经元细胞株（HT 22）和斑马鱼海马辐射损伤的保护作用。方法：观察VPA对HT 22海马神经元和斑马鱼海马辐射损伤的保护作用。测定细胞内活性氧（ROS）的产生、线粒体膜电位、谷胱甘肽（GSH）、丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性。核因子（红细胞衍生2）相关因子2（Nrf 2）和血红素加氧酶-1（HO-1）的表达也进行了测定。照射后1个月，对斑马鱼的认知行为进行评估。结果如下：VPA处理组能显著提高斑马鱼在致死剂量全身照射后1个月的存活率（300 mg/kg体重VPA：76.67%; 100 mg/kg体重VPA：56.7%）（P < 0.01）。VPA处理后，ROS生成减少（P < 0.01），MDA含量降低（P < 0.01），GSH含量升高（P< 0.01），SOD活性升高（P< 0.01）。VPA激活Nrf 2/HO-1通路，增加Nrf 2的核转位，增加HO-1的mRNA和蛋白表达（P < 0.01），保护神经元辐射损伤。Nrf 2基因的siRNA敲除阻止了VPA诱导的HT 22神经元细胞中辐射损伤的减轻，这在对照细胞中发现（40.09 +/- 1.76% vs. 41.14 +/-1.09%，P > 0.05）。VPA还改善了放射诱导的神经元损伤后的斑马鱼认知行为，如探索试验所测量的（对照组5.74 +/- 1.42 min vs.放射治疗16.39 +/- 4.03 min vs.放射治疗加VPA 7.18 +/- 1.79 min，P < 0.05）。结论：辐射暴露后ROS的产生有助于斑马鱼脑DNA损伤。VPA通过激活Nrf 2/HO-1通路抑制ROS生成，从而改善辐射诱导的神经元损伤后的认知行为。(C)2016年IBRO。由爱思唯尔有限公司出版。保留所有权利。
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 1 month 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 +/- 1.42 min vs. radiation therapy 16.39 +/- 4.03 min vs. radiation therapy plus VPA 7.18 +/- 1.79 min, 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. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.