Understanding sevoflurane-induced neurogenesis inhibition and cognitive dysfunction in children

Every year, millions of infants and children undergo surgery under general anesthesia in the world. Sevoflurane is a commonly used pediatric anesthetic. Its exposure during brain development has been shown to inhibit neurogenesis and cause cognitive dysfunction in animal models. Nevertheless, the underlying mechanisms remain elusive. Normal neurogenesis constitutes the neurobiological foundation for higher-order brain functions, such as learning and memory. Lipid metabolism is crucial for the regulation of neurogenesis.

"Carnitine palmitoyltransferase 1a (CPT1a) is a key molecule in regulating fatty acid β-oxidation (FAO), and PPARα serves as the principal regulatory factor of CPT1a. However, the potential alterations in FAO mediated by the peroxisome proliferator-activated receptor α (PPARα)/CPT1a pathway in neural stem/progenitor cells (NSPCs) following sevoflurane exposure, and its potential role in sevoflurane-induced neurogenesis inhibition and cognitive dysfunction, remain unclear.

Methods

NSPCs, NE-4C cells, and postnatal day 7 rats were exposed to 3% sevoflurane for 6 hours. Immunohistochemistry was used to verify whether sevoflurane exposure inhibits neurogenesis. The Morris water maze was employed to explore whether sevoflurane exposure impairs cognitive function. Untargeted lipidomics, FAOBlue staining, RNA isolation and real-time reverse transcription polymerase chain reaction (RT-qPCR), western blotting, CPT1a enzyme activity assay, and immunohistochemistry were utilized to validate the impact of sevoflurane exposure on FAO in NSPCs. Octanoate pretreatment, CPT1a overexpression, PPARα agonist palmitoylethanolamide (PEA), and FAO substrate carnitine pretreatment were collectively employed to reveal the role of FAO and PPARα in NSPCs on sevoflurane-induced neurogenesis inhibition and cognitive impairment.

Sevoflurane exposure inhibited neurogenesis and impaired cognitive function. In NSPCs, sevoflurane exposure caused extensive changes in lipid metabolism intermediates, inhibited the mRNA expression of acyl-CoA oxidase 1 (ACOX1), acyl-CoA oxidase 3 (ACOX3), hydroxyacyl-CoA dehydrogenase beta subunit (HADHB), CPT1a, carnitine palmitoyltransferase 2 (CPT2), acyl-CoA dehydrogenase short-chain (ACADS), and solute carrier family 22 member 5 (SLC22A5), suppressed FAO activity, and decreased the protein expression and activity of CPT1a. Enhancing FAO activity in NSPCs attenuated sevoflurane-induced neurogenesis impairment. Overexpression of CPT1a rescued sevoflurane-induced inhibition of FAO activity and neurogenesis in NE-4C cells. Besides, sevoflurane exposure reduced the expression levels of PPARα in the nuclei of NSPCs and hippocampal tissue. Pretreatment with PEA increased the nuclear content of PPARα and the expression of CPT1a in NSPCs and the rat hippocampus after sevoflurane exposure. Moreover, pretreatment with PEA or the CPT1a substrate carnitine rescued the sevoflurane-induced decrease of FAO activity in NSPCs, inhibition of neurogenesis in vivo and in vitro, and the cognitive impairment.

Discussion

Previous work has not investigated whether or how FAO participates in sevoflurane-induced neurogenesis inhibition and cognitive decline. Our study showed that sevoflurane inhibited neurogenesis and impaired cognitive function likely by inhibiting FAO in NSPCs through the PPARα/CPT1a pathway.This study reveals a new potential mechanism of sevoflurane neurodevelopmental toxicity. Future research is needed to clarify the role of FAO in NSPCs in sevoflurane-induced neurogenesis inhibition and cognitive impairment, and to explore the mechanisms that execute this FAO-dependent effect.