Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration
Effects of L-dopa and other amino acids against paraquat-induced nigrostriatal degeneration
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DOI：
10.1046/j.1471-4159.2003.01621.x
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发表时间：
2003-04-01
影响因子：
4.7
通讯作者：
Di Monte, DA
中科院分区：
文献类型：
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作者：
McCormack, AL;Di Monte, DA
接触除草剂百草枯会导致小鼠大脑中选择性黑质纹状体变性和α-突触核蛋白聚集。本研究的目的是评估百草枯进入中枢神经系统的机制，特别是血脑屏障中性氨基酸转运蛋白（系统L载体）底物对百草枯蓄积和神经毒性的影响。使用百草枯抗体，在注射除草剂的小鼠中脑中观察到强烈的免疫反应性。这种免疫反应性被废除的管理L-缬氨酸或L-苯丙氨酸，两个系统L基板，百草枯曝光之前。这些氨基酸的预处理完全防止百草枯诱导的黑质纹状体多巴胺能细胞的损失和硫代黄素S阳性细胞内沉积物的形成。有趣的是，抗帕金森病药物左旋多巴通过相同的中性氨基酸载体穿过血脑屏障，在百草枯之前30分钟给药时也具有神经保护作用。与此相反，如果动物（i）用d-缬氨酸（L-缬氨酸的生物学无活性d-异构体）或L-赖氨酸（碱性而非中性氨基酸载体的底物）预处理，或（ii）在接触百草枯24小时后注射L-多巴，百草枯诱导的毒性则不受影响。数据与百草枯神经毒性中跨血脑屏障摄取的关键作用一致，并表明膳食元素（如氨基酸）或治疗剂（如左旋多巴）可能会改变针对黑质纹状体系统的毒物的影响。
Exposure to the herbicide paraquat causes selective nigrostriatal degeneration and aggregation of alpha-synuclein in the mouse brain. The purpose of this study was to assess mechanisms of paraquat entry into the CNS and, in particular, the effects of substrates of the blood-brain barrier (BBB) neutral amino acid transporter (System L carrier) on paraquat accumulation and neurotoxicity. Using a paraquat antibody, robust immunoreactivity was observed in the midbrain of mice injected with the herbicide. This immunoreactivity was abolished by administration of L-valine or L-phenylalanine, two System L substrates, immediately before paraquat exposure. Pre-treatment with these amino acids completely protected against paraquat-induced loss of nigrostriatal dopaminergic cells and formation of thioflavine S-positive intracellular deposits. Interestingly, the anti-parkinsonian drug L-dopa, which is transported across the BBB through the same neutral amino acid carrier, was also neuroprotective when administered 30 min prior to paraquat. In contrast, paraquat-induced toxicity was unaffected if animals (i) were pre-treated with d-valine, the biologically inactive d-isomer of L-valine, or with L-lysine, a substrate of the basic rather than the neutral amino acid carrier, or (ii) were injected with L-dopa 24 h after paraquat exposure. Data are consistent with a critical role of uptake across the BBB in paraquat neurotoxicity, and suggest that dietary elements (e.g. amino acids) or therapeutic agents (e.g. L-dopa) may modify the effects of toxicants targeting the nigrostriatal system.