Acrylamide (AA) constitutes an important industrial chemical agent and well-known neurotoxin. However, the mechanism underlying AA-mediated neurotoxicity is extremely complicated and controversial. In this study, we found that activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its subsequent downstream inflammatory responses plays an important role in AA-induced neurotoxicity mechanisms. In vitro experiments revealed that AA (2.5 mM) induced BV2 microglial cytotoxicity and triggered NLRP3 inflammasome activation along with downstream proinflammatory cytokine interleukin-1β and interleukin-18 expression. Treatment with inhibitor or NLRP3 siRNA efficiently protected BV2 microglial cells against AA-induced cytotoxicity and reversed NLRP3 inflammasome activation and its mediated inflammatory reaction. Similarly, AA exposure (50 mg/kg) for 10 consecutive days caused significant activation of NLRP3 inflammasomes and neuroinflammation in C57BL/6 mice, whereas inhibiting these effects through specific NLRP3 inflammasome blocker MCC950 (5 mg/kg) intervention or NLRP3 knock-out significantly ameliorated AA-induced ataxia, cerebellar Purkinje cells degeneration, and apoptosis. Furthermore, we demonstrated that antagonism of NLRP3 could also up-regulate the Nrf2 signalling pathway and related antioxidant genes. In conclusion, our findings indicate that activation of the NLRP3 inflammasome pathway is involved in AA-induced neurotoxicity, whereas MCC950 treatment or NLRP3 knock-out could effectively protect against AA-induced neurotoxic injury through the inhibition of neuroinflammation and activation of the Nrf2 antioxidant pathway. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target, with drugs designed to specifically inhibit this pathway potentially providing new avenues for preventing or ameliorating AA poisoning.

中文翻译：

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NLRP3 炎症小体抑制可减弱丙烯酰胺在体外和体内诱导的亚急性神经毒性。

丙烯酰胺 (AA) 是一种重要的工业化学试剂和众所周知的神经毒素。然而，AA 介导的神经毒性的机制极其复杂和有争议。在这项研究中，我们发现 NLR 家族 pyrin 结构域 3 (NLRP3) 炎症小体的激活及其随后的下游炎症反应在 AA 诱导的神经毒性机制中起着重要作用。体外实验表明，AA (2.5 mM) 诱导 BV2 小胶质细胞的细胞毒性并触发 NLRP3 炎症小体激活以及下游促炎细胞因子白细胞介素 1β 和白细胞介素 18 的表达。用抑制剂或 NLRP3 siRNA 治疗有效保护 BV2 小胶质细胞免受 AA 诱导的细胞毒性并逆转 NLRP3 炎症小体激活及其介导的炎症反应。相似地，连续 10 天的 AA 暴露 (50 mg/kg) 导致 C57BL/6 小鼠 NLRP3 炎症小体和神经炎症的显着激活，而通过特定的 NLRP3 炎症小体阻滞剂 MCC950 (5 mg/kg) 干预或 NLRP3 敲除来抑制这些影响显着改善AA 诱导的共济失调、小脑浦肯野细胞变性和细胞凋亡。此外，我们证明了 NLRP3 的拮抗作用也可以上调 Nrf2 信号通路和相关的抗氧化基因。总之，我们的研究结果表明 NLRP3 炎症小体通路的激活与 AA 诱导的神经毒性有关，而 MCC950 治疗或 NLRP3 敲除可以通过抑制神经炎症和激活 Nrf2 抗氧化通路有效地防止 AA 诱导的神经毒性损伤. 所以，