Abstract：
Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson\'s disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.
摘要：
百草枯（PQ）是一种广谱除草剂，对人类健康有害。累积证据加强了PQ暴露与帕金森病（PD）发展之间的关联。然而,PQ诱导的神经毒性的潜在机制和有效干预措施尚不清楚.在这项研究中,C57BL/6J小鼠用PQ治疗（i.p.，10mg/kg,每周两次）和褪黑激素（i.g.，20mg/kg,每周两次)持续8周。结果表明，褪黑素预处理可以保护PQ引起的C57BL/6J小鼠的运动缺陷和中脑多巴胺能神经元损伤。在分离的初级中脑神经元和SK-N-SH细胞中，细胞活力降低，ROS总水平的升高，褪黑素减轻了PQ引起的轴突线粒体转运缺陷和线粒体功能障碍。筛选后表达驱动轴突线粒体运输的主马达,数据显示，褪黑素拮抗了PQ降低的KIF5A在小鼠中脑和SK-N-SH细胞中的表达。使用体外KIF5A过表达模型，发现KIF5A过表达抑制了PQ引起的SK-N-SH细胞的神经毒性和线粒体功能障碍。此外,MTNR1B（MT2）受体拮抗剂的应用，4-P-PDOT,显著抵消褪黑素对PQ诱导的神经毒性的保护作用。Further,在C57BL/6J小鼠中，Kif5a敲低减少了褪黑素诱导的运动缺陷和针对PQ的神经元损伤的缓解。本研究建立了环境神经毒物暴露与PD病因之间的因果关系，并为PD的发病机理提供了有效的干预靶标。
