Liu Xi, Cui Changmeng, Sun Wenxue, Meng Junjun, Guo Jinxiu, Wu Linlin, Chen Beibei, Liao Dehua, Jiang Pei
Department of Pharmacy, Linfen People's Hospital, Linfen, China.
Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China.
J Toxicol. 2023 Aug 5;2023:5660481. doi: 10.1155/2023/5660481. eCollection 2023.
It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and verification. The aims of this study were to clarify the molecular mechanism underlying PTX-induced neurotoxicity by combining and metabolomics studies and provide new targets for the prevention and treatment of PTX-induced neurotoxicity.
In the study, a PTX-induced neurotoxicity mouse model was established by intraperitoneal injection of PTX (6 mg/kg every three days) for two consecutive weeks. After verification by water maze tests and HE staining of pathological sections, hippocampal metabolites were measured and the differential metabolites and related metabolic pathways were identified by multivariate statistical analysis. In the study, we investigated the effects of PTX on mouse hippocampal neuron cells, assessing the concentration and time of administration by MTT assays. After modeling, the relevant metabolites in the TCA cycle were quantified by targeted metabolomics using stable isotope labeling. Finally, the key enzymes of the TCA cycle in tissues and cells were verified by RT-PCR.
Administration of PTX to model mice resulted in neurological damage, shown by both water-maze tests and hippocampal tissue sections. Twenty-four metabolites and five associated metabolic pathways were found to differ significantly between the hippocampal tissues of the model and control groups. These included metabolites and pathways related to the TCA cycle and pyruvate metabolism. Metabolomics analysis using stable isotope labeling showed significant changes in metabolites associated with the TCA cycle compared with the control group ( < 0.05). Finally, RT-PCR verified that the expression of key enzymes in the TCA cycle was changed to different degrees in both hippocampal tissues and cells.
Our results showed that PTX neurotoxicity in hippocampal tissue and neuron cells was associated with inhibition of the TCA cycle. This inhibition leads to brain insufficiency and impaired metabolism, resulting in various neurotoxic symptoms.
众所周知，紫杉醇（PTX）诱导的神经毒性严重影响患者的生活质量，是减少化疗剂量甚至停止化疗的主要原因。目前的数据有限，实践和验证需要更多信息。本研究的目的是通过结合代谢组学研究来阐明PTX诱导神经毒性的分子机制，并为PTX诱导神经毒性的防治提供新靶点。
在研究中，通过连续两周腹腔注射PTX（每三天6mg/kg）建立PTX诱导神经毒性的小鼠模型。经水迷宫试验和病理切片HE染色验证后，测定海马代谢物，并通过多元统计分析鉴定差异代谢物和相关代谢途径。在研究中，我们研究了PTX对小鼠海马神经元细胞的影响，通过MTT试验评估给药浓度和时间。建模后，使用稳定同位素标记通过靶向代谢组学对三羧酸循环中的相关代谢物进行定量。最后，通过RT-PCR验证组织和细胞中三羧酸循环的关键酶。
对模型小鼠给予PTX导致神经损伤，水迷宫试验和海马组织切片均显示了这一点。发现模型组和对照组海马组织之间有24种代谢物和5条相关代谢途径存在显著差异。这些包括与三羧酸循环和丙酮酸代谢相关的代谢物和途径。使用稳定同位素标记的代谢组学分析显示，与对照组相比，三羧酸循环相关代谢物有显著变化（P<0.05）。最后，RT-PCR验证三羧酸循环关键酶在海马组织和细胞中的表达均有不同程度的变化。
我们的结果表明，海马组织和神经元细胞中的PTX神经毒性与三羧酸循环的抑制有关。这种抑制导致脑功能不足和代谢受损，从而产生各种神经毒性症状。
