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.

Graphical abstract

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.

中文翻译：

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综合脂质组学和转录组学分析揭示克拉霉素诱导小鼠大脑皮层甘油磷脂代谢的改变

克拉霉素（CLA）已广泛用于治疗细菌感染。研究揭示了接受 CLA 治疗的患者对中枢神经系统的不良影响；然而，相关的潜在机制仍相当不清楚。根据我们的研究，应用综合脂质组学和转录组学分析来探索 CLA 对神经行为的影响。在小鼠的旷场试验以及高架十字迷宫试验中，CLA 治疗会引起剂量依赖性的焦虑样行为。采用转录组和基于 LC/MS-MS 的代谢组来研究 CLA 如何影响脂质组学分析以及大脑皮层的代谢途径。CLA 暴露极大地扰乱了甘油磷脂代谢和脂肪酸的碳链长度。通过使用全转录组测序，我们发现 CLA 显着下调 CEPT1 和 CHPT1（参与甘油磷脂合成的两种关键酶）的 mRNA 表达，支持了脂质组学分析的发现。此外，CLA 在体外引起神经元形态和功能的变化，这支持了有关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 的神经行为效应有关。我们的研究结果有助于理解 CLA 对中枢神经系统产生不良影响的机制。

图形概要

1.克拉霉素治疗引起小鼠焦虑样行为，在旷场和高架十字迷宫试验中均出现剂量依赖性反应；

2.克拉霉素暴露主要扰乱小鼠大脑皮层甘油磷脂代谢；

3.应用克拉霉素显着减弱参与甘油磷脂合成最后一步的CEPT1和CHPT1基因表达；

4.甘油磷脂代谢组学的改变可能与克拉霉素引起的神经行为异常有关。