Qingdao Municipal Center for Disease Control & Prevention, Qingdao Institute of Preventive Medicine, Qingdao, 266033, China; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Department of Anesthesiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116023, China.
Toxicol Lett. 2021 Oct 1;349:1-11. doi: 10.1016/j.toxlet.2021.05.008. Epub 2021 May 27.
Pesticides exposure can lead to damage of dopaminergic neurons, which are associated with increased risk of Parkinson's disease (PD). However, the etiology of PD remains poorly understood and no therapeutic strategy is available. Previous studies suggested the involvement of NLRP3 inflammasome in the onset of PD. This study was designed to investigate whether glibenclamide, an inhibitor of NLRP3 inflammasome, could offer a reliable protective strategy for PD in a mouse PD model induced by paraquat and maneb. We found that glibenclamide exerted potent neuroprotection against paraquat and maneb-induced upregulation of α-synuclein, dopaminergic neurodegeneration and motor impairment in brain of mice. Mechanistically, glibenclamide treatment blocked NLRP3 inflammasome activation evidenced by reduced expressions of NLRP3, activated caspase-1 and mature interleukin-1β in glibenclamide co-treated mice compared with those in paraquat and maneb group mice. Furthermore, glibenclamide treatment mitigated paraquat and maneb-induced microglial M1 proinflammatory response and nuclear factor-κB activation in mice. Finally, the increased superoxide production, lipid peroxidation, protein levels of NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) induced by paraquat and maneb were all attenuated by glibenclamide. Overall, our findings demonstrated that glibenclamide protected dopaminergic neurons in a mouse PD model induced by combined exposures of paraquat and maneb through suppression of NLRP3 inflammasome activation, microglial M1 polarization and oxidative stress.
农药暴露可导致多巴胺能神经元损伤，与帕金森病（PD）风险增加有关。然而，PD 的病因仍不清楚，也没有有效的治疗策略。先前的研究表明，NLRP3 炎性小体参与了 PD 的发病机制。本研究旨在探讨格列本脲（NLRP3 炎性小体抑制剂）是否能在百草枯和代森锰诱导的 PD 小鼠模型中为 PD 提供可靠的保护策略。我们发现，格列本脲对百草枯和代森锰诱导的α-突触核蛋白、多巴胺能神经退行性变和小鼠大脑运动功能障碍具有强大的神经保护作用。在机制上，与百草枯和代森锰组相比，格列本脲治疗组小鼠 NLRP3 炎性小体的激活受到抑制，NLRP3、活化的 caspase-1 和成熟的白细胞介素-1β的表达降低。此外，格列本脲治疗减轻了百草枯和代森锰诱导的小鼠小胶质细胞 M1 前炎性反应和核因子-κB 激活。最后，百草枯和代森锰诱导的超氧阴离子产生、脂质过氧化、NADPH 氧化酶 2（NOX2）和诱导型一氧化氮合酶（iNOS）的蛋白水平增加均被格列本脲减弱。总之，我们的研究结果表明，格列本脲通过抑制 NLRP3 炎性小体激活、小胶质细胞 M1 极化和氧化应激，保护百草枯和代森锰联合暴露诱导的 PD 小鼠模型中的多巴胺能神经元。
