美國羅徹斯特大學的Phillip Rappold等通過體外培養(yǎng)細胞及小鼠實驗研究了百草枯引發(fā)神經(jīng)毒性的機制，其研究結(jié)果近日發(fā)表在美國國家科學院院刊（Proceedings of the National Academy of Sciences）上,。
越來越多的流行病學證據(jù)表明,，百草枯（PQ）可以增加發(fā)生帕金森病的風險,，該病的典型病理改變?yōu)槎喟桶飞窠?jīng)元的減少，具有多巴胺轉(zhuǎn)運體（DAT）基因變異的個體對該病較為易感,。
Phillip Rappold等通過體外實驗和小鼠實驗來研究PQ是否通過DAT途徑進入多巴胺,，進而產(chǎn)生神經(jīng)毒性。
研究者發(fā)現(xiàn)PQ在二價陽離子狀態(tài)下（PQ2+）并不被表達DAT的細胞所接納,。但在大腦內(nèi),，其被還原劑或酶轉(zhuǎn)換為一價陽離子狀態(tài)（PQ+），PQ+ DAT運送至神經(jīng)元內(nèi),，進而引起神經(jīng)元氧化應激及細胞死亡,。
與此相反，DAT活性受損的細胞或小鼠則對PQ介導的神經(jīng)毒性有抵抗作用,。
此外,，作者還發(fā)現(xiàn)PQ+ 有機陽離子轉(zhuǎn)運體3（Oct3）運送至非多巴胺細胞內(nèi)。更令人驚奇的是,，Oct3缺失的小鼠對PQ更加敏感,。
研究者指出，這一現(xiàn)象可能是由于非多巴胺細胞對PQ+ 的攝取減少,，導致可被多巴胺細胞攝取PQ+ 數(shù)量增加所致,。這一發(fā)現(xiàn)表明DAT和Oct3的相互作用調(diào)節(jié)百草枯的神經(jīng)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.
