Abstract
BackgroundChildren who are exposed to anesthesia multiple times may undergo cognitive impairment during development. The underlying mechanism has been revealed as anesthesia-induced cognitive deficiency in young rodents and monkeys. However, the molecular mechanism of sevoflurane-induced neural development toxicity is unclear.MethodsBy combining RNA sequencing analysis of macaques’ prefrontal cortex and human neural differentiation, this study investigates the mechanism of sevoflurane-induced neurotoxicity in primates.ResultsThe level of dual specificity protein phosphatase 4 (Dusp4) was significantly downregulated in non-human primates after sevoflurane treatment. We further uncovered the dynamical expression of Dusp4 during the human neural differentiation of human embryonic stem cells and found that knockdown of Dusp4 could significantly inhibit human neural differentiation.ConclusionThis study indicated that Dusp4 is critically involved in the sevoflurane-induced inhibition of neural differentiation in non-human primate and the regulation of human neural differentiation. It also suggested that Dusp4 is a potential therapeutic target for preventing the sevoflurane-induced neurotoxicity in primates.
Highlights
For young children, the safety of general anesthesia exposure is a critical health issue, which receives widespread attention (Rappaport et al, 2011; Vutskits and Xie, 2016)
We performed multiple sevoflurane exposures in infant rhesus macaques on postnatal day 7 (P7), P14, and P28 repetitively, with each exposure lasting for 4 h per time as shown in a previous study (Alvarado et al, 2017)
We confirmed the downregulation of Dual specificity protein phosphatase 4 (Dusp4) in prefrontal cortex of rhesus macaques after sevoflurane treatment by Quantitative RT-PCR (qPCR)
Summary
The safety of general anesthesia exposure is a critical health issue, which receives widespread attention (Rappaport et al, 2011; Vutskits and Xie, 2016). Sevoflurane, the most commonly used anesthetic in children, is reported to induce neurotoxicity and cognitive impairment in non-human primates and rodents (Shen et al, 2013; Zhang et al, 2013; Yi et al, 2016). Aberrant neural differentiation is ascribed to cognitive impairment in young rodents (Cho et al, 2015). One study even demonstrated that sevoflurane inhibited neural differentiation (Zhang et al, 2019b). In consideration of the different developmental specificity and timing between primates and rodents (Xue et al, 2013), the mechanism of the sevoflurane upon neural differentiation requires further elucidation in primates. The underlying mechanism has been revealed as anesthesia-induced cognitive deficiency in young rodents and monkeys. The molecular mechanism of sevoflurane-induced neural development toxicity is unclear
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