L-3,4-二羟基苯丙氨酸（l -DOPA或左旋多巴）是目前治疗帕金森病（PD）症状最常用的药物。穿过血脑屏障后，它被神经元细胞酶促转化为多巴胺，并恢复耗尽的内源性神经递质水平。l -DOPA 容易发生自动氧化，其降解的活性中间体（包括活性氧 (ROS)）与细胞损伤有关。在这项研究中，我们研究了氧张力如何影响l -DOPA 稳定性。我们施加的氧张力与哺乳动物大脑中的氧张力相当，并证明 2% 的氧气几乎完全阻止了其自动氧化。l -DOPA甚至发挥ROS清除功能。进一步的机制分析表明，l -DOPA 重新编程线粒体代谢并减少氧化磷酸化，使线粒体膜去极化，诱导还原性谷氨酰胺代谢，并耗尽 NADH 池。这些结果为了解左旋多巴在生理氧水平下的细胞效应及其神经毒性提供了新的线索，而生理氧水平与体外常氧条件非常不同。
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Impairment of neuronal mitochondrial function by l-DOPA in the absence of oxygen-dependent auto-oxidation and oxidative cell damage
L-3,4-Dihydroxyphenylalanin (l-DOPA or levodopa) is currently the most used drug to treat symptoms of Parkinson’s disease (PD). After crossing the blood–brain barrier, it is enzymatically converted to dopamine by neuronal cells and restores depleted endogenous neurotransmitter levels. l-DOPA is prone to auto-oxidation and reactive intermediates of its degradation including reactive oxygen species (ROS) have been implicated in cellular damage. In this study, we investigated how oxygen tension effects l-DOPA stability. We applied oxygen tensions comparable to those in the mammalian brain and demonstrated that 2% oxygen almost completely stopped its auto-oxidation. l-DOPA even exerted a ROS scavenging function. Further mechanistic analysis indicated that l-DOPA reprogrammed mitochondrial metabolism and reduced oxidative phosphorylation, depolarized the mitochondrial membrane, induced reductive glutamine metabolism, and depleted the NADH pool. These results shed new light on the cellular effects of l-DOPA and its neuro-toxicity under physiological oxygen levels that are very distinct to normoxic in vitro conditions.