Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid
Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid
复制标题
DOI：
10.1046/j.1471-4159.2001.00335.x
复制
发表时间：
2001-06-01
影响因子：
4.7
通讯作者：
Moroni, F
中科院分区：
文献类型：
--
作者：
Chiarugi, A;Meli, E;Moroni, F
3OH-犬尿氨酸和喹啉酸是色氨酸代谢物，在相对升高的浓度下，能够在体外和体内引起神经元死亡。在混合皮层细胞的原代培养物中，当暴露时间从24小时延长到72小时时，导致显著程度的神经毒性的这些化合物的最小浓度从100 μ M降低到1 μ M。NMDA受体拮抗剂和一氧化氮合酶或聚（ADP-核糖）聚合酶抑制剂减少喹啉酸，但不是3OH-犬尿氨酸毒性。相反，自由基清除剂，半胱天冬酶抑制剂和环孢菌素优先减少3OH-犬尿氨酸神经毒性。这些观察结果表明，喹啉酸导致坏死，而3OH-犬尿氨酸暴露的神经元主要死于细胞凋亡。与这种可能性一致，我们发现喹啉酸暴露的培养物中ATP水平下降得比3OH-犬尿氨酸暴露的培养物中更快，并且多聚腺苷酸暴露的培养物中ATP水平下降得比3OH-犬尿氨酸暴露的培养物中更快。（ADP-核糖）聚合物，聚（ADP-核糖）聚合酶的活性，更丰富的喹啉酸的核比那些3OH-犬尿氨酸暴露的神经元。由于3OH-犬尿氨酸和喹啉酸的生理浓度的微小变化可能导致神经元死亡，我们的数据表明，这些代谢产物在几个神经决定的发病机制中起着关键作用。
3OH-Kynurenine and quinolinic acid are tryptophan metabolites able to cause, at relatively elevated concentrations, neuronal death in vitro and in vivo. In primary cultures of mixed cortical cells, the minimal concentration of these compounds leading to a significant degree of;neurotoxicity decreased from 100 to 1 muM, when the exposure time was prolonged from 24 to 72 h. NMDA receptor antagonists and inhibitors of nitric oxide synthase or poly(ADP-ribose) polymerase reduced quinolinic acid, but not 3OH-kynurenine toxicity. In contrast, scavengers of free radicals, caspase inhibitors and cyclosporin preferentially reduced 3OH-kynurenine neurotoxicity. These observations suggest that quinolinic acid causes necrosis, whereas 3OH-kynurenine-exposed neurons primarily die in apoptosis, In line with this possibility, we found that ATP levels decreased more rapidly in quinolinate- than in 3OH-kynurenine-exposed cultures and that poly(ADP-ribose) polymer, the product of poly(ADP-ribose) polymerase activity, was more abundant in the nuclei of quinolinic acid than in those of 3OH-kynurenine-exposed neurons. Because minor changes in the physiological concentrations of 3OH-kynurenine and quinolinic acid may cause neuronal death, our data suggest that these metabolites play a key role in the pathogenesis of several neurological decisions.