Abstract
Background: The anesthetics inhibit neural differentiation, induce neuron loss and cognitive impairment in young animals. However, the underlying mechanisms of anesthesia on neural differentiation are unknown.Methods: Embryonic stem cells (ESCs) and mice received sevoflurane anesthesia. RNA sequencing; gene expression of mRNAs, LncRNAs and miRNAs; over-expression and RNA interference of genes; flow cytometry; real-time quantity PCR and Western blot were used in the studies. RNA pull-down assay and PCR were employed to detect any miRNA that attached to Rik-203. The binding of miRNA with mRNA of BDNF was presented by the luciferase assay.Results: Here we found that LncRNA Riken-203(Rik-203) was highly expressed in mice brain and was upregulated during neural differentiation. Sevoflurane decreased the amount of Rik-203 in mice brain. Knockdown of Rik-203 repressed the neural differentiation derived from mouse embryonic stem cell and downregulated the neural progenitor cells markers Sox1 and Nestin. RNA pull-down showed that miR-466l-3p was highly bound to Rik-203. Inhibition of miR-466l-3p restored the neural differentiation repressed by Rik-203 knockdown. Brain derived neurotrophic factor (BDNF), which was downregulated by sevoflurane, was also directly targeted by miR-466l-3p. Overexpression of BDNF restored the neural differentiation repressed by miR-466l-3p and Rik-203 knockdown.Conclusion: Our study suggested that sevoflurane related LncRNARik-203 facilitates neural differentiation by inhibiting miR-466l-3p's ability to reduce BDNF levels.
Highlights
The widespread and growing use of anesthesia in children makes its safety a major health issue of interest [1], reviewed in [2]
We found that Long non-coding RNAs (LncRNAs) Rik-203 contributes to anesthesia induced inhibition of neural differentiation [26]
We performed the induction of neural differentiation from mouse embryonic stem cells (ESCs) 46c and found that the amount of Rik-203 was upregulated significantly during the neural differentiation from mESCs to neural stem cells (NSCs) (Figure 1C)
Summary
The widespread and growing use of anesthesia in children makes its safety a major health issue of interest [1], reviewed in [2] It has become a matter of even greater concern as evidence shows that multiple exposures to anesthesia and surgery may induce cognitive impairment in children [3,4,5,6,7,8], and that anesthetics may induce neurotoxic damage and cognitive impairment in young animals [1, 9,10,11,12,13]. Contradictory reports exist [8, 14, 15], and single and short time exposure to anesthesia and surgery is not associated with cognitive impairment in children [16, 17]. The underlying mechanisms of anesthesia on neural differentiation are unknown
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