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

• Published in: CNS neuroscience & therapeutics Vol. 30; no. 2; pp. e14612 - n/a
• Main Authors: Zuo, Yong, Xie, Jinhong, Zhang, Xue, Thirupathi, Anand, Liu, Xiaopeng, Zhang, Di, Zhang, Jianhua, Shi, Zhenhua
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2024
• Subjects: Anesthesia; Anesthetics; Animals; Antibodies; Apoptosis; Brain; Bromodeoxyuridine; Bromodeoxyuridine - metabolism; Carbon dioxide; Cell cycle; Cell Proliferation; Cognition; Cognitive ability; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - metabolism; cognitive impairment; Cortex; DNA biosynthesis; DNA methylation; Drinking water; General anesthesia; Hippocampus; Hippocampus - metabolism; Homeostasis; Humans; Immunofluorescence; Infants; Iron; Iron - metabolism; Iron Deficiencies; Iron deficiency; Mice; Mice, Inbred C57BL; Neural stem cells; Neural Stem Cells - metabolism; neurodevelopment; Neurodevelopmental disorders; Neurons; Neurons - metabolism; Neurotoxicity; Nutrient deficiency; Oligodendrocytes; Pax6 protein; Sevoflurane; Sevoflurane - toxicity; United States > US; Massachusetts; Germany; iron metabolism; cognitive impairment; sevoflurane; neurodevelopment
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14612

Aims Numerous studies on animals have shown that exposure to general anesthetics in infant stage may cause neurocognitive impairment. However, the exact mechanism is not clear. The dysfunction of iron metabolism can cause neurodevelopmental disorders. Therefore, we investigated the effect of iron metabolism disorder induced by sevoflurane (Sev) on cognitive function and the proliferation of neural precursor cells (NPCs) and neural stem cells (NSCs) in infant mice. Methods C57BL/6 mice of postnatal day 14 and neural stem cells NE4C were treated with 2% Sev for 6 h. We used the Morris water maze (MWM) to test the cognitive function of infant mice. The proliferation of NPCs was measured using bromodeoxyuridine (BrdU) label and their markers Ki67 and Pax6 in infant brain tissues 12 h after anesthesia. Meanwhile, we used immunohistochemical stain, immunofluorescence assay, western blot, and flow cytometer to evaluate the myelinogenesis, iron levels, and cell proliferation in cortex and hippocampus or in NE4C cells. Results The results showed that Sev significantly caused cognitive deficiency in infant mice. Further, we found that Sev inhibited 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 downregulating FtH and FtL expression and upregulating the TfR1 expression in the cortex and hippocampus, which dramatically suppressed the proliferation of NSCs and NPCs as indicated by decreasing the colocalization of Pax6+ and BrdU+ cells, and caused the decrease in the number of neurons. Interestingly, iron supplementation before anesthesia significantly improved iron deficiency in cortex and hippocampus and cognitive deficiency induced by Sev in infant mice. Iron therapy inhibited the decrease of MBP expression, iron levels in neurons and oligodendrocytes, and DNA synthesis of Pax6+ cells in hippocampus induced by Sev. Meanwhile, the number of neurons was partially recovered in hippocampus. Conclusion The results from the present study demonstrated that Sev‐induced iron deficiency might be a new mechanism of cognitive impairment caused by inhaled anesthetics in infant mice. Iron supplementation before anesthesia is an effective strategy to prevent cognitive impairment caused by Sev in infants. Sevoflurane inhibits the proliferation of neural precursor cells by causing iron deficiency in infant mice which further inducescognitive dysfunction. Iron supplementation before anesthesia is an effective strategy to prevent cognitive impairment caused by Sev in infants.