Zhao W, Richardson J S, Mombourquette M J, Weil J A
Department of Pharmacology, University of Saskatchewan, Saskatoon, Canada.
Free Radic Biol Med. 1995 Jul;19(1):21-30. doi: 10.1016/0891-5849(95)00007-k.
Oxygen-based free radicals have been shown to play a major role in the acute destruction of neurons following cerebral ischemia and may be involved in the chronic neurodegeneration seen in Parkinson's disease, Alzheimer's disease, and other conditions characterized by the progressive death of neurons in the central nervous system. Drugs belonging to a group of antioxidant compounds, collectively known as the lazaroids, have strong neuroprotective effects in experimental models of acute ischemia. However, the specific mechanisms by which these drugs reduce the harmful actions of free radicals have not been established. Using electron paramagnetic resonance (EPR) spectroscopy with spin trapping, we investigated the interaction of U-74500A, a first-generation lazaroid, and U-78517F, a second-generation lazaroid, with two species of oxygen-based free radicals in aqueous solution and with the stable nitrogen-based free radical diphenylpicrylhydrazyl in dimethyl sulfoxide. Superoxide radicals were generated by the action of xanthine oxidase on hypoxanthine. Hydroxyl radicals were generated by the Fenton reaction involving aqueous ferrous iron and hydrogen peroxide. Both lazaroids reduce the EPR signal of all three radicals, but the drugs differ in potency and relative radical selectivity. These observations are consistent with the lazaroids being scavengers of oxygen-based and nitrogen-based free radicals and suggest that the neuroprotective actions of the lazaroids in cerebral ischemia may involve direct interactions of the lazaroids with several different species of free radicals.
基于氧的自由基已被证明在脑缺血后神经元的急性破坏中起主要作用，并且可能参与帕金森病、阿尔茨海默病以及其他以中枢神经系统神经元进行性死亡为特征的疾病中的慢性神经退行性变。属于一组抗氧化化合物（统称为拉扎罗类药物）的药物，在急性缺血的实验模型中具有很强的神经保护作用。然而，这些药物减少自由基有害作用的具体机制尚未明确。我们使用自旋捕获电子顺磁共振（EPR）光谱法，研究了第一代拉扎罗类药物U-74500A和第二代拉扎罗类药物U-78517F与水溶液中的两种基于氧的自由基以及二甲基亚砜中稳定的基于氮的自由基二苯基苦味酰基肼的相互作用。超氧阴离子自由基由黄嘌呤氧化酶作用于次黄嘌呤产生。羟自由基由涉及亚铁离子水溶液和过氧化氢的芬顿反应产生。两种拉扎罗类药物均降低了所有三种自由基的EPR信号，但这两种药物在效力和相对自由基选择性方面存在差异。这些观察结果与拉扎罗类药物作为基于氧和基于氮的自由基清除剂一致，并表明拉扎罗类药物在脑缺血中的神经保护作用可能涉及拉扎罗类药物与几种不同自由基的直接相互作用。
