Sevoflurane causes cognitive impairment by inducing iron deficiency and inhibiting proliferation of neural precursor cells in infant mice

Anesthesia can induce cognitive impairment in young rodents. However, the exact mechanism is not clear. Iron deficiency can cause neurodevelopment disorder. Therefore, we investigated the effect of iron deficiency induced by sevoflurane (Sev) on cognitive function in infant mice. C57BL/6 mice of postnatal day 14 and neural stem cells (NSCs) NE4C were treated with 2% Sev for 6h. We used the Morris water maze (MWM) to test the cognitive function of infant mice. Then, we used immunohistochemical stain, immunofluorescence assay, western blot, and flow cytometer to evaluate the myelinogenesis, iron levels, cell proliferation in cortex and hippocampus or in NE4C cells in vivo or in vitro. We found that Sev significantly caused cognitive deficiency. Further, we found that Sev inhibited the oligodendrocytes proliferation and myelinogenesis by decreasing MBP and CC-1 expression and iron levels. Meanwhile, Sev also induced the iron deficiency in neurons, and NSCs by down-regulating FtH and FtL expression and up-regulating the TfR1 expression in the cortex and hippocampus, which dramatically suppressed the proliferation of NSCs and neural progenitor cells(NPCs) by decreasing the expression of Pax6 and Ki67, and caused the decrease of counts of neurons. Interestingly, iron supplementation before anesthesia significantly improved iron deficiency and cognitive deficiency induced by Sev in infant mice. In conclusion, these data suggested that Sev-induced iron deficiency might be a new mechanism of cognitive impairment caused by inhaled anesthetics in infant mice. The iron supplementation before anesthesia is an effective strategy to prevent cognitive impairment caused by Sev in infants.