Anesthesia is unavoidable in surgical procedures. However, whether the general anesthetics are neurotoxic to immature brains remains undefined. Neurodevelopmental impairment induced by anesthesia has been a critical health issue and topic of concern. This review summarizes recent progress made in clinical and preclinical studies to provide useful suggestions and potential therapeutic targets for the protection of the immature brain. On the one hand, clinical researchers continue the debate about the effect of single and multiple exposures to anesthesia on developing brains. On the other hand, preclinical researchers focus on exploring the mechanisms of neurotoxic effects of general anesthesia on immature brains and seeking novel solutions. Rodent models have always been used in preclinical studies, but it is still unclear whether the mechanisms observed in rodent models have clinical relevance. Compared with these models, non-human primates (NHPs) are more genetically similar to humans. However, few research institutions in this area can afford to use NHP models in their studies. One way to address both problems is by combining single-cell sequencing technologies to screen differential gene expression in NHPs and perform in vivo validation in rodents. The mechanism of anesthesia-induced neurotoxicity still requires further elucidation in primates.

Sevoflurane has become one of the most widely used volatile anesthetics in pediatric surgery. However, sevoflurane exposure may interfere with dendritic development and synaptogenesis, resulting in brain function impairment. The PI3K/AKT/mTOR pathway plays an important role in dendritic development and synaptic plasticity. Here we investigated whether sevoflurane exposure would affect the morphological proportions of dendritic spines in developing mouse and explored the role of the change of plasticity of dendritic spines in sevoflurane-induced neurodevelopmental toxicity. The related signaling pathway was also examined. C57BL/6 mice at postnatal day (PND) 7 were exposed to 2% sevoflurane for 3 h. The PI3k/AKT/mTOR agonist IGF-1 or the mTOR phosphorylation inhibitor KU0063794 was intraperitoneally injected 30 min before sevoflurane or O2 exposure at PND7. Hippocampi were harvested 6 h after sevoflurane exposure. Western blotting was applied to measure the protein expression of PI3K/AKT/mTOR pathway phosphorylation. At PND14, brains from all groups were harvested for Golgi staining, and the morphology of dendritic spines of hippocampal neurons was observed by an oil immersion lens. When the mice grew to adolescence (PND48), fine motor function was measured by the Beam walking test. Here we showed that exposure to 2% sevoflurane for 3 h decreased the proportion of thin dendritic spines and increased the proportion of mushroom dendritic spines, but not changed the density of the dendritic spines. Sevoflurane exposure also suppressed the phosphorylation of the PI3K/AKT/mTOR pathway in immature mice hippocampi, and eventually led to long-term fine motor dysfunction. Meanwhile, IGF-1 pretreatment could rescue and KU0063794 pretreatment could aggravate the impairment induced by sevoflurane. In conclusion, sevoflurane exposure may cause a change of proportions of the types of dendritic spines through impacting the phosphorylation expression of the PI3K/AKT/mTOR pathway, and eventually led to long-term fine motor dysfunction in developing mouse.