National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Medical School, West China Hospital, Sichuan University, #1 Keyuan Road, Gaopeng Street, High-tech Development Zone, Chengdu, 610041, People's Republic of China.
Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China.
Cell Biol Toxicol. 2023 Jun;39(3):771-793. doi: 10.1007/s10565-021-09646-5. Epub 2021 Aug 30.
Clarithromycin (CLA) has been widely used in the treatment of bacterial infection. Research reveals the adverse effects on the central nervous system among patients receiving CLA treatment; whereas, a relevant underlying mechanism remains considerably unclear. According to our research, an integrated lipidomic and transcriptomic analysis was applied to explore the effect of CLA on neurobehavior. CLA treatment caused anxiety-like behaviors dose-dependently during open field as well as elevated plus maze trials on mice. Transcriptomes and LC/MS-MS-based metabolomes were adopted for investigating how CLA affected lipidomic profiling as well as metabolic pathway of the cerebral cortex. CLA exposure greatly disturbed glycerophospholipid metabolism and the carbon chain length of fatty acids. By using whole transcriptome sequencing, we found that CLA significantly downregulated the mRNA expression of CEPT1 and CHPT1, two key enzymes involved in the synthesis of glycerophospholipids, supporting the findings from the lipidomic profiling. Also, CLA causes changes in neuronal morphology and function in vitro, which support the existing findings concerning neurobehavior in vivo. We speculate that altered glycerophospholipid metabolism may be involved in the neurobehavioral effect of CLA. Our findings contribute to understanding the mechanisms of CLA-induced adverse effects on the central nervous system. 1. Clarithromycin treatment caused anxiety-like behavior with dose-dependent response both in the open field and elevated plus maze test in mice; 2. Clarithromycin exposing predominately disturbed the metabolism of glycerophospholipids in the cerebral cortex of mice; 3. Clarithromycin application remarkably attenuated CEPT1 and CHPT1 gene expression, which participate in the last step in the synthesis of glycerophospholipids; 4. The altered glycerophospholipid metabolomics may be involved in the abnormal neurobehavior caused by clarithromycin.
克拉霉素（CLA）被广泛用于治疗细菌感染。研究表明，接受 CLA 治疗的患者中枢神经系统会出现不良反应，但相关的潜在机制仍不清楚。根据我们的研究，采用综合脂质组学和转录组学分析来探讨 CLA 对神经行为的影响。CLA 处理在小鼠的旷场和高架十字迷宫试验中导致焦虑样行为呈剂量依赖性。采用转录组学和基于 LC/MS-MS 的代谢组学来研究 CLA 如何影响大脑皮层的脂质组学特征和代谢途径。CLA 暴露极大地扰乱了甘油磷脂代谢和脂肪酸的碳链长度。通过全转录组测序，我们发现 CLA 显著下调了参与甘油磷脂合成的两个关键酶 CEPT1 和 CHPT1 的 mRNA 表达，这支持了脂质组学分析的结果。此外，CLA 在体外引起神经元形态和功能的变化，这支持了体内神经行为的现有发现。我们推测，甘油磷脂代谢的改变可能与 CLA 对中枢神经系统的神经行为作用有关。我们的研究结果有助于理解 CLA 对中枢神经系统不良影响的机制。
