美国罗彻斯特大学的Phillip Rappold等通过体外培养细胞及小鼠实验研究了百草枯引发神经毒性的机制，其研究结果近日发表在美国国家科学院院刊（Proceedings of the National Academy of Sciences）上。
越来越多的流行病学证据表明，百草枯（PQ）可以增加发生帕金森病的风险，该病的典型病理改变为多巴胺神经元的减少，具有多巴胺转运体（DAT）基因变异的个体对该病较为易感。
Phillip Rappold等通过体外实验和小鼠实验来研究PQ是否通过DAT途径进入多巴胺，进而产生神经毒性。
研究者发现PQ在二价阳离子状态下（PQ2+）并不被表达DAT的细胞所接纳。但在大脑内，其被还原剂或酶转换为一价阳离子状态（PQ+），PQ+ DAT运送至神经元内，进而引起神经元氧化应激及细胞死亡。
与此相反，DAT活性受损的细胞或小鼠则对PQ介导的神经毒性有抵抗作用。
此外，作者还发现PQ+ 有机阳离子转运体3（Oct3）运送至非多巴胺细胞内。更令人惊奇的是，Oct3缺失的小鼠对PQ更加敏感。
研究者指出，这一现象可能是由于非多巴胺细胞对PQ+ 的摄取减少，导致可被多巴胺细胞摄取PQ+ 数量增加所致。这一发现表明DAT和Oct3的相互作用调节百草枯的神经毒性。（生物谷bioon.com）
doi:10.1073/pnas.1115141108
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Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3
Phillip M. Rappold, Mei Cui, Adrianne S. Chesser,Jacqueline Tibbett, Jonathan C. Grima, Lihua Duan, Namita Sen,Jonathan A. Javitch, and Kim Tieu.
The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ2+ is not a substrate for DAT; however, when converted to the monovalent cation PQ+ by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ+. In addition to DAT, PQ+ is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ+ being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ2+/PQ+ redox cycling.
