Montine T J, Picklo M J, Amarnath V, Whetsell W O, Graham D G
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Exp Neurol. 1997 Nov;148(1):26-33. doi: 10.1006/exnr.1997.6662.
Progression of Parkinson's disease has been associated with several biochemical changes in the substantia nigra including increased oxidative challenge, catechol oxidation, and inhibition of mitochondrial complex I activity. Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized catechols, have been identified as markers of catechol oxidation in brain tissue. We have examined the neurotoxicity of a series of cysteinylcatechols. Of the compounds examined, only 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was specifically cytotoxic to differentiated P19 neuroglial cultures. Cysdopac also was neurotoxic to pyramidal neurons in organotypic cultures of hippocampus, and this effect was ablated by selective N-methyl-D-aspartate (NMDA) receptor antagonists. In vitro, cysdopac was a potent inhibitor of mitochondrial complex I activity. However, electrophysiologic experiments failed to demonstrate NMDA receptor agonist activity for cysdopac, nor did cysdopac inhibit glutamate uptake. These results showed that cysdopac was the most potent neurotoxin of this series of cysteinylcatechols and suggest that cysdopac may function as an indirect excitotoxin, potentially via inhibition of mitochondrial respiration.
帕金森病的进展与黑质中的多种生化变化有关，包括氧化应激增加、儿茶酚氧化以及线粒体复合体I活性受到抑制。半胱氨酰儿茶酚是由半胱氨酸对氧化型儿茶酚进行亲核加成反应形成的，已被确定为脑组织中儿茶酚氧化的标志物。我们检测了一系列半胱氨酰儿茶酚的神经毒性。在所检测的化合物中，只有5-S-半胱氨酰-3,4-二羟基苯乙酸（cysdopac）对分化的P19神经胶质细胞培养物具有特异性细胞毒性。Cysdopac对海马器官型培养物中的锥体神经元也具有神经毒性，并且这种效应可被选择性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂消除。在体外，cysdopac是线粒体复合体I活性的强效抑制剂。然而，电生理实验未能证明cysdopac具有NMDA受体激动剂活性，cysdopac也未抑制谷氨酸摄取。这些结果表明，cysdopac是该系列半胱氨酰儿茶酚中最有效的神经毒素，并提示cysdopac可能作为一种间接兴奋性毒素发挥作用，可能是通过抑制线粒体呼吸来实现的。
