Chen Hongjin, Liao Chenlong, Yang Xiaosheng, Zhou Han, Wu Yiwei, Sun Qiuyang, Li Shuo, Zhang Wenchuan
Department of Neurosurgery, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Genet. 2023 Mar 23;14:1151340. doi: 10.3389/fgene.2023.1151340. eCollection 2023.
Mechanical allodynia (MA) is one of the leading clinical symptoms of painful diabetic peripheral neuropathy (PDPN), which is a primary reason for non-traumatic amputations, foot ulceration, and gait abnormalities in patients with diabetes. However, the pathogenic mechanisms of MA have not yet been fully elucidated, and there is no effective treatment. This study aims to study the potential pathogenetic mechanisms of MA and to provide targets for the therapy of MA. A single intraperitoneal injection of streptozotocin induced type 1 diabetes in rat models. Subsequently, rats were divided into the control group, the diabetic group without MA, and the diabetic group with MA based on weekly behavioral assays. The differentially expressed lipids in the sciatic nerve of each group were detected using untargeted lipidomics, and the differentially expressed genes in the sciatic nerve of each group were detected by transcriptomics. The pathogenesis of MA was predicted using integrated analysis and validated by immunofluorescence staining and transmission electron microscopy. Untargeted lipidomics revealed the accumulation of a more severe lipid in MA rats. Transcriptomics results suggested that differentially expressed genes in MA rats were primarily related to lipid droplets and myelin sheath. Integrated analysis results indicated that the downregulation of Cytochrome P450 1A2 (CYP1A2) expression was closely linked to lipid metabolism disorders. Immunofluorescence staining demonstrated that down-regulation of CYP1A2 expression occurred in MA rats. Transmission electron microscopy results showed that more severe lipid droplet accumulation and myelin sheath degeneration occurred in MA rats. Our findings imply that the downregulation of CYP1A2 expression leads to disorders of lipid metabolism and further leads to lipid droplet accumulation and myelin sheath degeneration, which might ultimately lead to the development of MA. Therefore, our study contributes to promoting the understanding of the molecular mechanisms of MA and providing potential targets for the clinical treatment of MA.
机械性异常性疼痛（MA）是疼痛性糖尿病周围神经病变（PDPN）的主要临床症状之一，这是糖尿病患者非创伤性截肢、足部溃疡和步态异常的主要原因。然而，MA的发病机制尚未完全阐明，且尚无有效的治疗方法。本研究旨在探讨MA的潜在发病机制，并为MA的治疗提供靶点。通过单次腹腔注射链脲佐菌素诱导大鼠模型患1型糖尿病。随后，根据每周的行为学检测，将大鼠分为对照组、无MA的糖尿病组和有MA的糖尿病组。采用非靶向脂质组学检测每组坐骨神经中差异表达的脂质，通过转录组学检测每组坐骨神经中差异表达的基因。采用综合分析预测MA的发病机制，并通过免疫荧光染色和透射电子显微镜进行验证。非靶向脂质组学显示MA大鼠中一种更严重的脂质积累。转录组学结果表明，MA大鼠中差异表达的基因主要与脂滴和髓鞘有关。综合分析结果表明，细胞色素P450 1A2（CYP1A2）表达下调与脂质代谢紊乱密切相关。免疫荧光染色显示MA大鼠中CYP1A2表达下调。透射电子显微镜结果显示，MA大鼠中脂滴积累和髓鞘变性更严重。我们的研究结果表明，CYP1A2表达下调导致脂质代谢紊乱，进而导致脂滴积累和髓鞘变性，这可能最终导致MA的发生。因此，我们的研究有助于增进对MA分子机制的理解，并为MA的临床治疗提供潜在靶点。
