Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime

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.