School of Public Health/MOE Key Laboratory of Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, 130 Dong'an Road, Shanghai, 200032, China.
Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, 201203, China.
Sci Rep. 2020 Oct 20;10(1):17757. doi: 10.1038/s41598-020-74916-x.
Paraquat (PQ), a widely used herbicide, could cause neurodegenerative diseases, yet the mechanism remains incompletely understood. This study aimed to investigate the direct effect of PQ on NSC in vivo and its possible mechanism. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control once a week for 2 weeks, and sacrificed 1 week after the last PQ injection. Furthermore, extra experiments with Tauroursodeoxycholic Acid (TUDCA) intervention were performed to observe the relationship between ER stress, neuroinflammation and the neural stem cell (NSC) impairment. The results showed that 20 mg/kg PQ caused the NSC number decrease in both subgranular zones (SGZ) and subventricular zone (SVZ). Further analysis indicated that the 20 mg/kg PQ suppressed the proliferation of NSC, without affecting the apoptosis. Moreover, 20 mg/kg PQ also induced ER stress in microglia and caused neuroinflammation in SGZ and SVZ. Interestingly, the ER stress inhibitor could simultaneously ameliorate the neuroinflammation and NSC reduction. These data suggested that increased ER stress in microglia might be a possible pathway for PQ-induced neuroinflammation and NSC impairment. That is a previously unknown mechanism for PQ neurotoxicity.
百草枯（PQ）是一种广泛使用的除草剂，可导致神经退行性疾病，但机制尚不完全清楚。本研究旨在探讨 PQ 对体内神经干细胞（NSC）的直接影响及其可能的机制。成年 C57BL/6 小鼠每周皮下注射 2mg/kg PQ、20mg/kg PQ 或载体对照一次，最后一次 PQ 注射后 1 周处死。此外，还进行了牛磺熊脱氧胆酸（TUDCA）干预的额外实验，以观察 ER 应激、神经炎症与神经干细胞（NSC）损伤之间的关系。结果表明，20mg/kg PQ 导致 SGZ 和 SVZ 中 NSC 数量减少。进一步分析表明，20mg/kg PQ 抑制了 NSC 的增殖，而不影响其凋亡。此外，20mg/kg PQ 还诱导了小胶质细胞中的 ER 应激，并导致 SGZ 和 SVZ 中的神经炎症。有趣的是，ER 应激抑制剂可同时改善神经炎症和 NSC 减少。这些数据表明，小胶质细胞中 ER 应激的增加可能是 PQ 诱导的神经炎症和 NSC 损伤的一种可能途径。这是 PQ 神经毒性的一个以前未知的机制。
