School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China.
School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China.
Ecotoxicol Environ Saf. 2020 Sep 1;200:110733. doi: 10.1016/j.ecoenv.2020.110733. Epub 2020 May 22.
Paraquat (1,1'-dimethyl-4,4'-bipyridium dichloride, PQ), a non-selective and efficient herbicide, causes neuroinflammation, neurodegeneration and memory dysfunction. However, adverse effects of PQ on the neuroimmune interactions have rarely been investigated. Female adult C57/BL6 mice were divided into 3 groups and treated with PQ (intraperitoneal injection, 1 mg/kg or 5 mg/kg) or the vehicle (an equivalent volume of 0.9% saline) every two days, at day 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, for a total of 14 doses. We evaluated blood-brain barrier (BBB) integrity and PQ concentrations during the course of PQ exposure and tested interleukin-1β (IL-1β) concentrations in dentate gyrus (DG) after 28 days PQ exposure. In addition, memory function, neural stem cells (NSCs) proliferation, neurogenesis and microglia polarization were analyzed after PQ exposure. Furthermore, mice were intraperitoneal injections of anti-IL-1β during 5 mg/kg PQ exposure to test the rule of IL-1β. Blood-brain barrier (BBB) permeability and PQ concentrations increased gradually during PQ exposure (n = 6). Moreover, memory function, NSCs proliferation and neurogenesis were impaired after 5 mg/kg PQ exposure (n = 6). Further analyses revealed that 'classically' activated (M1) microglia and IL-1β concentrations in DG were increased after 5 mg/kg PQ treatment (n = 6). Moreover, we found that neutralization of IL-1β partly restored PQ-induced NSCs impairments and memory dysfunction (n = 6). In conclusion, our results revealed that PQ induced NSCs impairments and memory dysfunction in adult mice, which was related to the release of IL-1β by M1-polarized microglia in DG. These findings may help understand the neurotoxic effect of PQ.
百草枯（1,1'-二甲基-4,4'-联吡啶二氯化物，PQ）是一种非选择性和高效的除草剂，可引起神经炎症、神经退行性变和记忆功能障碍。然而，PQ 对神经免疫相互作用的不良影响很少被研究。将雌性成年 C57/BL6 小鼠分为 3 组，用 PQ（腹腔注射，1mg/kg 或 5mg/kg）或载体（等体积 0.9%生理盐水）每两天处理一次，在第 1、3、5、7、9、11、13、15、17、19、21、23、25、27 天，共 14 次。我们在 PQ 暴露过程中评估血脑屏障（BBB）的完整性和 PQ 浓度，并在 28 天 PQ 暴露后测试齿状回（DG）中的白细胞介素-1β（IL-1β）浓度。此外，在 PQ 暴露后分析记忆功能、神经干细胞（NSCs）增殖、神经发生和小胶质细胞极化。此外，在 5mg/kg PQ 暴露期间，小鼠腹腔注射抗 IL-1β 以测试 IL-1β 的规律。在 PQ 暴露期间，血脑屏障（BBB）通透性和 PQ 浓度逐渐增加（n=6）。此外，5mg/kg PQ 暴露后，记忆功能、NSCs 增殖和神经发生受损（n=6）。进一步分析表明，5mg/kg PQ 处理后 DG 中的“经典”激活（M1）小胶质细胞和 IL-1β 浓度增加（n=6）。此外，我们发现中和 IL-1β 部分恢复了 PQ 诱导的 NSCs 损伤和记忆功能障碍（n=6）。总之，我们的结果表明，PQ 诱导成年小鼠 NSCs 损伤和记忆功能障碍，这与 DG 中 M1 极化小胶质细胞释放 IL-1β有关。这些发现可能有助于了解 PQ 的神经毒性作用。
