Abstract：
Acrylamide (ACR) is a common neurotoxicant that can induce central-peripheral neuropathy in human beings. ACR from occupational setting and foods poses a potential threat to people\'s health. Purkinje cells are the only efferent source of cerebellum, and their output is responsible for coordinating motor activity. Recent studies have reported that Purkinje cell injury is one of the earliest neurotoxicity at any dose rate of ACR. However, the mechanism underlying ACR-mediated damage to Purkinje cells remains unclear. This research aimed to investigate whether necroptosis is involved in ACR-induced Purkinje cell death and its regulatory mechanism. In this study, rats were treated with ACR (40 mg/kg/every other day) for 6 weeks to establish an animal model of ACR neuropathy. Furthermore, an intervention experiment was achieved by rapamycin (RAPA), which is commonly used to activate mitophagy and maintain mitochondrial homeostasis. The results demonstrated ACR exposure caused necroptosis of Purkinje cells, mitochondrial dysfunction, and inflammatory response. By contrast, RAPA alleviated mitochondrial dysfunction and inhibited activation of necroptosis signaling pathway following ACR. In conclusion, our findings suggest that mitochondrial dysfunction and activation of necroptotic signaling are associated with the loss of Purkinje cells in ACR poisoning, which can be a potential therapeutic target for ACR neurotoxicity.
摘要：
丙烯酰胺（ACR）是一种常见的神经毒物，可引起人类的中枢-周围神经病。来自职业环境和食物的ACR对人们的健康构成潜在威胁。浦肯野细胞是小脑唯一的传出来源,它们的输出负责协调运动活动。最近的研究报道，浦肯野细胞损伤是ACR在任何剂量率下最早的神经毒性之一。然而,ACR介导的Purkinje细胞损伤的潜在机制尚不清楚.本研究旨在探讨坏死是否参与ACR诱导的浦肯野细胞死亡及其调控机制。在这项研究中,用ACR(40mg/kg/隔天)治疗大鼠6周,建立ACR神经病变动物模型。此外，通过雷帕霉素（RAPA）进行干预实验，通常用于激活线粒体自噬和维持线粒体稳态。结果表明，ACR暴露导致浦肯野细胞坏死，线粒体功能障碍，和炎症反应。相比之下,RAPA减轻ACR后线粒体功能障碍并抑制坏死凋亡信号通路的激活。总之,我们的研究结果表明，线粒体功能障碍和坏死信号的激活与ACR中毒中Purkinje细胞的丢失有关，这可能是ACR神经毒性的潜在治疗靶点。
