Protective mechanisms of endogenous bioactive molecules on neuronal death associated with neurodegenerative disorders

我们关注内源性低分子量物质作为大脑对抗谷氨酸诱导的神经元死亡的内在保护机制。(1)血清芬地酸是一种从胎牛血清中分离出来的新物质，能显著降低谷氨酸的神经毒性。血清芬地酸抑制NO供体诱导的神经元死亡，但不影响谷氨酸受体介导的电流反应。血清芬地酸还能抑制羟基自由基的产生，抑制百草枯和过氧化氢诱导的神经元死亡。二甲基亚砜是血清芬地酸中的一个结构单元，具有类似的作用，但二甲基亚砜的有效浓度是血清芬地酸的3000倍左右，这表明血清芬地酸具有独立于自由基清除活性的神经保护作用。(2)我们测试了几种神经类固醇的神经保护作用，作为内源性物质，其物理化学性质与血清芬地酸相似。硫酸孕烯醇酮加重NMDA神经毒性，而硫酸孕烯醇酮抑制NMDA神经毒性。这些作用可归因于这些化合物直接调节NMDA受体通道。(3)研究了维生素E类似物的神经保护作用。生育三烯醇对过氧化氢诱导的神经元死亡具有显著的保护作用，而α-生育酚则没有作用。生育三烯醇还能抑制超氧化物、一氧化氮和谷胱甘肽耗竭诱导的神经元死亡。α-生育三烯醇可抑制司陶孢素诱导的细胞死亡。维生素E类似物的几个成员被证明通过独立于其抗氧化作用的机制来阻止细胞凋亡。(4)我们发现包括多奈哌齐在内的乙酰胆碱酯酶抑制剂显著抑制谷氨酸神经毒性。多奈哌齐长时间处理神经元至少24小时后出现神经保护作用，并通过刺激烟碱乙酰胆碱受体介导。

We focused on endogenous low-molecular-weight substances as intrinsic protective mechanisms of the brain against glutamate-induced neuronal death. (1)Serofendic acid, a novel substance identified from fetal calf serum, markedly attenuated glutamate neurotoxicity. Serofendic acid inhibited NO donor-induced neuronal death, but did not affect glutamate receptor-mediated current responses. Serofendic acid also prevented generation of hydroxyl radical, and inhibited neuronal death induced by paraquat and hydrogen peroxide. Dimethylsulfoxide, a structural unit contained in serofendic acid, exhibited similar effects, but the effective concentrations of dimethylsulfoxide were about 3000 times as high as those of serofendic acid, suggesting that serofendic acid possesses neuroprotective actions independent of radical-scavenging activity. (2)We tested neuroprotective effects of several neurosteroids, as endogenous substances whose physicochemical properties resemble those of serofendic acid. Pregnenolone sulfate exacerbated, whereas pregnanolone sulfate inhibited, NMDA neurotoxicity. These effects were attributable to direct modulation of NMDA receptor channels by these compounds. (3)We examined neuroprotective activities of vitamin E analogs. Tocotrienols provided a significant protective effect against hydrogen-peroxide induced neuronal death, whereas α-tocopherol was without effect. Tocotrienols also inhibited induction of neuronal death by superoxide, NO as well as depletion of glutathione. Staurosporine-induced cell death was inhibited by α-tocotrienol. Several members of vitamin E analogs were shown to block apoptosis by mechanims independent of their antioxidant actions. (4)We found that acetylcholinesterase inhibitors including donepezil markedly inhibited glutamate neurotoxicity. The neuroprotective action emerged after prolonged treatment of neurons with donepezil for at least 24 h, and was mediated by stimulation of nicotinic acetylcholine receptors.