Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury
Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury
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DOI：
10.1007/s11064-015-1602-5
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发表时间：
2015-06
影响因子：
4.4
通讯作者：
Haibo Wang;Jin Wang;Qi Yang;Xinwei Zhang;Peng Gao;Sheng-long Xu;Xiao-li Sun;Yukun Wang
中科院分区：
文献类型：
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作者：
Haibo Wang;Jin Wang;Qi Yang;Xinwei Zhang;Peng Gao;Sheng-long Xu;Xiao-li Sun;Yukun Wang
次声引起中枢神经系统的功能紊乱和结构损伤。然而，几乎没有抗次声药物存在，并且它们是无效的。据报道，硝酰基氮氧自由基是良好的抗氧化剂，其作为超氧化物歧化酶模拟物并直接与活性氧物种反应，如·OH、H2 O2和O2 −。我们的前期研究表明，硝酰基氮氧自由基L-NNNBP对APP/PS1 AD大鼠模型中的β-淀粉样蛋白沉积和记忆缺陷具有良好的保护作用。本研究的目的是寻找一组新的抗次声药物，并确定潜在的药理作用的硝酰基氮氧自由基对次声诱导的神经元损伤在体内。合成了一种新的稳定的硝酰基氮氧自由基NRbt，并对其晶体结构进行了表征。NR bt和阳性对照药物tempol的抗氧化损伤作用结果表明，与次声暴露前相比，NR bt和阳性对照药物tempol能显著提高大鼠肾脏SOD、CAT活性和GSH水平，降低MDA水平。而且NRbt对这些生化指标活性或水平的调节能力优于tempol。结果表明，NRbt和tempol均能显著改善次声所致的大鼠Morris水迷宫学习记忆障碍，但tempol组与NRbt组、tempol组和NRbt组相比，路径长度和逃避潜伏期无显著性差异（P> 0.05）。NRbt和tempol能显著抑制次声诱导的大鼠海马神经元凋亡。结果表明，与次声暴露组相比，NRbt（40 mg/kg）或Tempol（40 mg/kg）预处理组Bcl-2表达上调，Bax和caspase-3表达下调。这些结果表明，新合成的硝酰基氮氧自由基，NRbt，可能是一种有效的抗次声药物，因为它能够抑制由次声暴露引起的自由基的氧化损伤。
Infrasound causes functional disorders and structural injury to the central nervous system. However, few anti-infrasound drugs exist, and they are inefficient. Nitronyl nitroxide radicals have been reported to be good antioxidants that act as superoxide dismutase mimics and directly react with reactive oxygen species, such as ·OH, H2O2, and O2∙−. Our previous research showed that the nitronyl nitroxide radical L-NNNBP has good protective effects against β-amyloid deposition and memory deficits in an AD rat model of APP/PS1. The objective of the present study was to find a new group of anti-infrasound drugs and determine the underlying pharmacological actions of nitronyl nitroxide radicals against infrasound-induced neuronal impairment in vivo. We synthesized a new stable nitronyl nitroxide radical, NRbt, and characterized its crystal structure. The results of the anti-oxidative damage effects of NRbt and the positive control drug tempol showed that they could significantly increase the SOD activity, CAT activity and GSH level and decrease the MDA level in rat hippocampi compared with infrasound exposure without pretreatment. Moreover, the ability of NRbt to regulate the activity or level of these biochemical markers was better than that of tempol. Our results showed that both NRbt and tempol significantly protected against the learning and memory impairments induced by infrasound exposure in a Morris water maze, but there were no significant differences in the path length or escape latency between the rats in the tempol group and the three NRbt groups (P> 0.05). In addition, the infrasound-induced neuronal apoptosis in rat hippocampi was significantly suppressed by NRbt and tempol. The results demonstrated that compared with the infrasound exposure group, the expression of Bcl-2 was up-regulated and the expressions of Bax and caspase-3 were down-regulated in rats pretreated with NRbt (40 mg/kg) or tempol (40 mg/kg). These results showed that the newly synthesized nitronyl nitroxide radical, NRbt, may be an effective anti-infrasound drug because of its capacity to inhibit the oxidative damage of free radicals induced by infrasound exposure.