Li Yunbo, Cao Zhuoxiao
Department of Pharmaceutical Science, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA.
Neurosci Lett. 2002 Sep 13;330(1):69-73. doi: 10.1016/s0304-3940(02)00444-5.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a seleno-organic compound with glutathione peroxidase-like activity, has been shown to be protective against brain ischemic injury and Parkinson's disease. This study was undertaken to investigate the protective effects of ebselen on oxidative DNA damage induced by dopamine in the presence of copper ions. Incubation of phiX-174 plasmid DNA with micromolar dopamine in the presence of Cu(II) resulted in a concentration-dependent induction of DNA strand breaks. Both a Cu(II)/Cu(I) redox cycle and H(2)O(2) formation were critically involved in the induction of DNA strand breaks by the dopamine/Cu(II) system. The presence of ebselen at micromolar concentrations led to a marked concentration-dependent inhibition of DNA strand breaks induced by the dopamine/Cu(II) system. Further studies showed that ebselen did not affect either the Cu(II)-mediated oxidation of dopamine to dopamine quinone or the reduction of Cu(II) to Cu(I) by dopamine. Instead, the presence of ebselen resulted in a marked decrease in the levels of H(2)O(2) derived from the Cu(II)-mediated oxidation of dopamine. Taken together, our results demonstrate for the first time that ebselen is able to inhibit the dopamine/Cu(II)-induced oxidative DNA damage, which appears to be attributable to the ability of ebselen to decrease the levels of H(2)O(2) derived from the dopamine/Cu(II) system. Since oxidative DNA damage has been implicated in the pathogenesis of various neurodegenerative diseases, the inhibition of oxidative DNA damage by ebselen may be responsible, at least partially, for its neuroprotective activities observed in both humans and experimental animals.
依布硒啉（2-苯基-1,2-苯并异硒唑-3(2H)-酮）是一种具有谷胱甘肽过氧化物酶样活性的有机硒化合物，已被证明对脑缺血损伤和帕金森病具有保护作用。本研究旨在探讨依布硒啉在铜离子存在下对多巴胺诱导的氧化性DNA损伤的保护作用。在Cu(II)存在的情况下，将phiX-174质粒DNA与微摩尔浓度的多巴胺一起孵育，会导致DNA链断裂呈浓度依赖性诱导。Cu(II)/Cu(I)氧化还原循环和H(2)O(2)的形成都与多巴胺/Cu(II)系统诱导的DNA链断裂密切相关。微摩尔浓度的依布硒啉的存在导致多巴胺/Cu(II)系统诱导的DNA链断裂受到明显的浓度依赖性抑制。进一步的研究表明，依布硒啉既不影响Cu(II)介导的多巴胺氧化为多巴胺醌，也不影响多巴胺将Cu(II)还原为Cu(I)。相反，依布硒啉的存在导致多巴胺Cu(II)介导的氧化产生的H(2)O(2)水平显著降低。综上所述，我们的结果首次证明依布硒啉能够抑制多巴胺/Cu(II)诱导的氧化性DNA损伤，这似乎归因于依布硒啉降低多巴胺/Cu(II)系统产生的H(2)O(2)水平的能力。由于氧化性DNA损伤与多种神经退行性疾病的发病机制有关，依布硒啉对氧化性DNA损伤的抑制作用可能至少部分地解释了其在人类和实验动物中观察到的神经保护活性。
