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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.

No 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.

No abstract