Department of Biology, University, Roma TRE, Roma, Italy .
DNA Cell Biol. 2012 Nov;31(11):1572-9. doi: 10.1089/dna.2011.1546. Epub 2012 Sep 28.
Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by decreased levels of the neurotransmitter dopamine (DA) in the striatum of the brain, as a result of degeneration of DA neurons. Levodopa (L-Dopa) crosses the blood-brain barrier and its administration replenishes the loss of DA in dopaminergic neurons in PD patients. Despite the evident beneficial effects, L-Dopa use may cause side effects and its toxicity found in in vitro assays has been attributed to the generation of reactive oxygen species (ROS): L-Dopa is converted to DA and its metabolism and autoxidation gives rise to quinones, semiquinones, and hydrogen peroxide. Despite this evidence, L-Dopa in some in vivo and in vitro experiments showed no toxic effects, or even antioxidant effects. Two major peripheral L-Dopa metabolic pathways, driven by the enzymes Aromatic L-amino acid decarboxylase (AADC) and catechol-O-methyl transferase (COMT), significantly deplete the amount of L-Dopa reaching the brain. The low bioavailability of L-Dopa may cause a wide variation in clinical response between patients. Strategies addressing to improve the bioavailability of L-Dopa include coadministering L-Dopa with carbidopa, a decarboxylase inhibitor, as multiple daily doses. We utilized catecholaminergic human neuroblastoma cells to study DNA damage and ROS production after L-Dopa and carbidopa treatments. Our data lead us to confirm that L-Dopa may have a protective effect on dopaminergic cells especially at certain concentrations, in particular, toward the production of ROS and their toxic effects on DNA. Furthermore in the combined treatment, with induction of ROS following administration of H(2)O(2), carbidopa is effective in reducing the damage caused by reactive oxygen intermediates both alone and in combination with L-Dopa.
帕金森病（PD）是最常见的神经退行性疾病之一，其特征是大脑纹状体中的神经递质多巴胺（DA）水平降低，这是由于 DA 神经元的退化。左旋多巴（L-Dopa）能穿过血脑屏障，其给药可补充 PD 患者中多巴胺能神经元中 DA 的损失。尽管左旋多巴的使用具有明显的有益效果，但它可能会引起副作用，并且在体外试验中发现的其毒性归因于活性氧（ROS）的产生：左旋多巴转化为 DA，其代谢和自动氧化会产生醌、半醌和过氧化氢。尽管有这些证据，但在一些体内和体外实验中，左旋多巴没有显示出毒性作用，甚至具有抗氧化作用。由芳香族 L-氨基酸脱羧酶（AADC）和儿茶酚-O-甲基转移酶（COMT）驱动的两个主要外周左旋多巴代谢途径，大大减少了到达大脑的左旋多巴的量。左旋多巴的低生物利用度可能导致患者之间的临床反应存在很大差异。旨在提高左旋多巴生物利用度的策略包括将左旋多巴与卡比多巴（一种脱羧酶抑制剂）联合给药，作为每日多次剂量。我们利用儿茶酚胺能人类神经母细胞瘤细胞来研究 L-Dopa 和卡比多巴处理后 DNA 损伤和 ROS 产生。我们的数据使我们能够确认左旋多巴对多巴胺能细胞可能具有保护作用，特别是在某些浓度下，特别是在产生 ROS 及其对 DNA 的毒性作用方面。此外，在联合治疗中，在用 H（2）O（2）给药诱导 ROS 后，卡比多巴在单独使用和与左旋多巴联合使用时均能有效降低活性氧中间体引起的损伤。
