Endogenous factors regulating neuronal death induced by radical stress
Endogenous factors regulating neuronal death induced by radical stress
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DOI：
10.1248/bpb.27.964
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发表时间：
2004-07-01
影响因子：
2
通讯作者：
Akaike, A
中科院分区：
文献类型：
--
作者：
Kume, T;Katsuki, H;Akaike, A
中枢神经系统（CNS）中的神经元易受活性氧（包括一氧化氮（NO））引起的自由基应激的影响。这些自由基在与缺血性脑损伤和广泛的神经退行性疾病相关的谷氨酸神经毒性中起关键作用。在我们以前的研究中，我们已经证明谷氨酸的神经毒性是由某些内源性物质如神经营养因子，烟碱乙酰胆碱，前列腺素和维生素调节的。基于这些发现，我们使用“神经保护因子”一词来表示具有抗谷氨酸神经毒性保护活性的内源性物质，并进一步寻找具有独特结构的候选物质。我们从胎牛血清中分离出一种新的神经保护物质，命名为血清芬地酸。该化合物对谷氨酸和NO供体诱导的神经毒性表现出有效的保护作用，而不抑制谷氨酸受体。电子自旋共振分析表明，serofendic酸没有直接清除NO的活性，但能够抑制产生的羟基自由基，一个假定的“执行者”自由基在一氧化氮介导的神经毒性级联反应。通过质谱和核磁共振光谱确定化学结构，并通过合成确认。该化合物是一种含硫的阿替烷型二萜类化合物，其结构在已知的内源性物质中是独特的。血清芬地酸的发现为研究促进中枢神经元存活的低分子生物活性因子提供了新的途径。
Neurons in the central nervous system (CNS) are vulnerable to radical stress caused by reactive oxygen species, including nitric oxide (NO). Those radicals play crucial roles in glutamate neurotoxicity associated with ischemic brain injury and a wide range of neurodegenerative disorders. In our previous studies, we have shown evidence suggesting that glutamate neurotoxicity is regulated by certain endogenous substances such as neurotrophins, nicotinic acetylcholine, prostanoids and vitamins. Based on those findings, we have used the term 'neuroprotective factor' for endogenous substances possessing protective activity against glutamate neurotoxicity, and have further searched for a candidate with unique structure. We isolated a novel neuroprotective substance named 'serofendic acid' derived from fetal calf serum. The compound exhibited potent protective action against neurotoxicity induced by glutamate and by an NO donor without inhibiting glutamate receptors. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO, but was capable of inhibiting the generation of a hydroxyl radical, a presumed 'executor' radical in the nitric oxide-mediated neurotoxic cascade. The chemical structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy, and was confirmed by synthesis. The structure was unique among known endogenous substances because the compound was a sulfur-containing atisane type diterpenoid. The discovery of serofendic acid may provide a new scope for the investigation of low-molecular weight bioactive factors promoting the survival of CNS neurons.