Mitochondrial dysfunction promotes the necroptosis of Purkinje cells in the cerebellum of acrylamide-exposed rats.

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.