Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood–brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS–MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.
Background: Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). SynDIG1 functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPARcontent; however, the role of SynDIG1 in MDD remains elusive. Methods: We used a chronic social defeat stress model to investigate the effects of the SynDIG1 in depression and the underlying mechanism. Findings: In the present study, we found that the expression of SynDIG1 was significantly increased in the neurons of the nucleus accumbens (NAc) of mice after chronic social defeat stress (CSDS). CSDS enhanced the interaction of SynDIG1 with GluA2 and promoted the surface expression of the AMPAR subunit GluA2. Knockdown of SynDIG1 weakened the surface expression of GluA2, reversed the increased dendrite spines, and alleviated depressive-like behaviors. Intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Interpretation: SynDIG1 promotes the surface expression of GluA2 in the NAc under CSDS, which promotes stress-induced dendritic remodeling and mediates depressive-like behaviors. Funding: This work was supported by grants from National Natural Science Foundation of China (Grants 81871043,82071494, 81272459), the National Science and Technology Major Project (2018ZX09201018-011, 2018ZX09201017-009), and “1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University”.Declaration of Interest: The authors declare no competing interests.Ethical Approval: All experimental procedures and animals use were performed as the guidelines approved by the Institutional Animal Care and Use Committee of Sichuan University.
Abstract Cefepime exhibits a broad spectrum of antimicrobial activity and thus is widely used for severe bacterial infection. Adverse effects on the central nervous system (CNS) have been reported in the patients treated with cefepime. Current explanation for the neurobehavioral effect of cefepime mainly attributes to its ability to across blood-brain barrier and to competitively bind to GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different time period, including 1 day, 3 days, 5 days, 7 days and 10 days, and then LC/MS-MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profiling and metabolic pathway. Repeated cefepime treatment time-dependently caused anxiety-like behavior accompanied with the reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile in the corpus striatum, and glycerophospholipid contributed to a large proportion among those significantly modified lipids. Cefepime also significantly modified acyl chain length and unsaturation of fatty acids. In addition, cefepime obviously altered the morphology of neurite, mitochondria and synaptic vesicles of striatal neuron in vitro . Collectively, our results show that cefepime reprograms glycerophospholipid metabolism of corpus striatum, which may underly its neurobehavioral effect.
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