| With the development of medical technology,more and more infants need general anesthesia for surgery,clinical examination or other intervention measures.At present,whether general anesthesia affects the neurodevelopment of infants is still an important and controversial issue.However,it is necessary to further evaluate the effects of narcotic drugs on long-term neurodevelopment of children and explore their specific mechanisms,which is of great significance for guiding clinical decision-making.Sevoflurane is one of the most commonly used inhalation anesthetics in infants and young children.Short-term or single exposure to sevoflurane in infants and young children has a weak effect on cognitive function,while long-term or repeated exposure may lead to cognitive impairment.Long non-coding RNA(LncRNA)Riken plays an important role in regulating the development and function of the nervous system,but whether it is involved in sevoflurane induced developmental neurotoxicity remains unclear.This study aims to clarify whether sevoflurane is involved in the occurrence of neuroinflammation induced by it by regulating the expression of LncRNA Riken,and to explore the specific mechanism of LncRNA Riken in the occurrence of neuroinflammation induced by sevoflurane.We first found sevoflurane induced an increasing level of interleukin-6 in the development brain of neonatal rats(P6),and then found the same results in N2a cells.Meanwhile,we found that sevoflurane increased the level of IL-6 in the hippocampus and decreased the level of LncRNA Riken.To further explore whether LncRNA Riken was involved in the increase of IL-6 induced by sevoflurane,we overexpressed LncRNA Riken before sevoflurane treatment.The results showed that overexpression of LncRNA Riken reduced the level of inflammatory cytokine IL-6.LncRNA Riken is mainly distributed in the cytoplasm and may function as a molecular sponge of microRNA(miRNA),thereby indirectly inhibiting the negative regulation of miRNA on target genes.Therefore,we explored the miRNA bound by LncRNA Riken and found that LncRNA Riken could bind to miR101a.Subsequently,by predicting miR101a target genes,we conducted GO functional and KEGG pathway enrichment analysis to analyze the biological processes and regulatory molecular pathways that target genes might participate in.Predictive analysis and dual luciferase assay confirmed that mitogenactivated protein kinase(MAPK)phosphatase 1(MKP-1)was the target gene of miR101a.We subsequently confirmed that sevoflurane reduced MKP-1 levels in the mice and N2a cells.MKP-1 can dephosphorylate threonine and tyrosine,so we measured phosphorylation levels in the related downstream pathways,and the result showed that decreasing MKP-1 can increase JNK phosphorylation in sevoflurane anesthetized mice and N2a cells.JNK inhibitor SP600125 reduced sevoflurane-induced the level of IL-6.In conclusion,sevoflurane down-regulates the expression of LncRNA Riken in the developing brain and promotes the increase of inflammatory cytokine IL-6.The downregulated expression of LncRNA Riken increased the negative regulation function of miR101a on its target gene MKP-1,and the phosphorylation level of JNK increased,leading to the occurrence of neuroinflammation in the development brain.This study provided a new theoretical basis for the mechanism of developmental neurotoxicity induced by sevoflurane.In addition,more basic studies and clinical trials should be conducted to explore the molecular mechanism of potential neurotoxicity on long-term cognitive function,which is of great significance to guide the clinical prevention and treatment of sevoflurane-induced neurodevelopmental injury in infants. |
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