BackgroundEmerging evidence indicates that long-time use of multiple antibiotics can induce cognitive dysfunction via gut dysbiosis. Cefazolin is often used for 3 to 5 days to prevent perioperative infection. This study is to detect the impact of perioperative use of cefazolin on inflammatory responses and postoperative cognition.MethodsThe anti-inflammatory effect of cefazolin was determined in mouse C8-B4 microglial cells treated with lipopolysaccharide (LPS). Interleukin (IL)-6 and IL-1β at 6 and 24 h after LPS treatment were detected. Six- to 8-week-old CD-1 mice were subjected to laparotomy. Cefazolin at 300 mg/kg was injected intraperitoneally 1 h before surgery and then once per day for 5 days after surgery. Their learning and memory were assessed by Barnes maze and fear conditioning tests which started 1 week after the surgery. The brain and colon were harvested 24 h and 6 days after surgery to determine inflammatory cytokines. The colon and its luminal contents were harvested 6 and 19 days after surgery for the determination of bacteria flora. Cefazolin concentrations in the serum and brain were measured 0.5, 1, and 2 h after cefazolin injection.ResultsIL-6 and IL-1β levels were decreased by 250 μg/ml cefazolin in the LPS-stimulated C8-B4 cells. Laparotomy increased the time for mice to identify the target hole in the Barnes maze on day 1 and day 8 after training sessions and reduced context-related freezing behavior in fear conditioning test. Cefazolin attenuated these surgical effects but reduced context-related freezing behavior in mice without surgery. IL-6 in the hippocampus and cerebral cortex, IL-1β in the cerebral cortex, and IL-6 and IL-1β in the serum and colon were increased 24 h after laparotomy. Cefazolin attenuated these effects. Cefazolin treatment for 5 days in mice without surgery induced colon dysbiosis and increased IL-6 and IL-1β in the colon and IL-1β in the cerebral cortex. Colon dysbiosis disappeared in mice treated with cefazolin alone but persisted in mice with surgery and cefazolin 19 days after surgery. High cefazolin concentrations in the serum but not in the brain were detected after cefazolin injection.ConclusionsThese results suggest that cefazolin has a direct anti-inflammatory effect and can attenuate surgery-induced postoperative memory and learning impairment in mice. Cefazolin alone may induce cognitive dysfunction possibly by transient gut dysbiosis in mice without surgery.

Background HCN1 channels have been identified as targets of ketamine to produce hypnosis. Volatile anesthetics also inhibit HCN1 channels. However, the effects of HCN1 channels on volatile anesthetics in vivo is still elusive. This study uses global and conditional HCN1 knockout mice to evaluate how HCN1 channels affect the actions of volatile anesthetics. Methods Minimum alveolar concentrations (MAC) of isoflurane and sevoflurane that induced immobility (MAC of immobility) and/or hypnosis (MAC of hypnosis) were determined in wild-type (WT) mice, global HCN1 channel knockout mice (HCN1−/−), floxed HCN1 channel gene (HCN1f/f) mice and forebrain-selective HCN1 channel knockout (HCN1f/f: cre) mice. Immobility of mice was defined as no purposeful reactions to tail-clamping stimulus and hypnosis was defined as loss of righting reflex (LORR). The amnestic effects of isoflurane and sevoflurane were evaluated by fear-potentiated startle in these four strains of mice. Results All MAC values were expressed as mean ± SEM. For MAC of immobility of isoflurane, no significant difference was found among wild-type, HCN1−/−, HCN1f/f and HCN1f/f: cre mice (all ~1.24-1.29% isoflurane). For both HCN1−/− and HCN1f/f: cre mice, the MAC of hypnosis for isoflurane (each ~1.05% isoflurane) were significantly increased over their nonknockout controls: HCN1−/− vs. wild-type (0.86±0.03%, P<0.001) and HCN1f/f: cre vs. HCN1f/f mice (0.84±0.03%, P<0.001); no significant difference was found between HCN1−/− and HCN1f/f: cre mice. For MAC of immobility of sevoflurane, no significant difference was found among wild-type, HCN1−/−, HCN1f/f and HCN1f/f: cre mice (all ~2.6-2.7% sevoflurane). For both HCN1−/− and HCN1f/f: cre mice, the MAC of hypnosis for sevoflurane (each ~1.90% sevoflurane) was significantly increased over their nonknockout controls: HCN1−/− vs. wild-type (1.58±0.05%, P<0.001) and HCN1f/f: cre vs. HCN1f/f mice (1.56±0.05%, P<0.001). No significant difference was found between HCN1−/− and HCN1f/f: cre mice. By fear-potentiated startle experiments, amnestic effects of isoflurane and sevoflurane were significantly attenuated in HCN1−/− and HCN1f/f: cre mice (both P<0.002 vs. wild-type or HCN1f/f mice). No significant difference was found between HCN1−/− and HCN1f/f: cre mice. Conclusions Forebrain HCN1 channels contribute to hypnotic and amnestic effects of volatile anesthetics, but HCN1 channels are not involved in the immobilizing actions of volatile anesthetics.

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Volatile anesthetics induce hyperactivity during induction while producing anesthesia at higher concentrations. They also bidirectionally modulate many neuronal functions. However, the neuronal mechanism is unclear. The effects of isoflurane on sodium channel currents were analyzed in acute mouse brain slices, including sodium leak (NALCN) currents and voltage-gated sodium channels (Na v) currents. Isoflurane at sub-anesthetic concentrations increased the spontaneous firing rate of CA3 pyramidal neurons, whereas anesthetic concentrations of isoflurane decreased the firing rate. Isoflurane at sub-anesthetic concentrations enhanced NALCN conductance but minimally inhibited Na v currents. Isoflurane at anesthetic concentrations depressed Na v currents and action potential amplitudes. Isoflurane at sub-anesthetic concentrations depolarized resting membrane potential (RMP) of neurons, whereas hyperpolarized the RMP at anesthetic concentrations. Isoflurane at low concentrations induced hyperactivity in vivo, which was diminished in NALCN knockdown mice. In conclusion, enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction.