Every year, millions of infants and children undergo surgery under general anesthesia around the world. Sevoflurane is a widely used pediatric anesthetic. Its exposure during brain development has been shown to inhibit neurogenesis and induce cognitive dysfunction in animal models. However, the underlying mechanisms remain elusive. Normal neurogenesis is 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 the regulation of fatty acid β-oxidation (FAO), and PPARα serves as the master regulator of CPT1a. peroxisome proliferator-activated receptor α (PPARα)/The CPT1a pathway in neural stem/progenitor cells (NSPCs) following sevoflurane exposure and its potential role in sevoflurane-induced inhibition of neurogenesis and cognitive dysfunction remains vague.
Methods
NSPCs, NE-4C cells, and postnatal day 7 rats were exposed to 3% sevoflurane for 6 h. Immunohistochemistry was used to verify whether sevoflurane exposure inhibited neurogenesis. The Morris water maze was used to investigate whether exposure to sevoflurane impairs cognition. Non-targeted lipidomics, FAOBlue staining, RNA isolation and real-time reverse transcription polymerase chain reaction (RT-qPCR), western blotting, CPT1a enzyme activity assay and immunohistochemistry were used to validate the effect of sevoflurane exposure on FAO NSPCs. Octanoate pretreatment, CPT1a overexpression, the PPARα agonist palmitoylethanolamide (PEA), and FAO carnitine substrate pretreatment were used collectively to reveal the role of FAO and PPARα in NSPCs in sevoflurane-induced neurogenesis inhibition and cognitive function.
Exposure to sevoflurane inhibited neurogenesis and impaired cognitive function. In NSPCs, exposure to sevoflurane induced extensive changes in intermediates of lipid metabolism, inhibited acyl-CoA oxidase 1 mRNA expression (ACOX1), acyl-CoA oxidase 3 (ACOX3), beta hydroxyacyl-CoA dehydrogenase subunit (HADHB), CPT1acarnitine palmitoyltransferase 2 (CPT2), short-chain acyl-CoA dehydrogenase (ACADS), and solute carrier family 22 members 5 (SLC22A5), suppressed FAO activity and reduced CPT1a protein expression and activity. Enhancement of FAO activity in NSPCs attenuated sevoflurane-induced disruption of neurogenesis. Overexpression of CPT1a rescued the sevoflurane-induced inhibition of FAO activity and neurogenesis in NE-4C cells. In addition, sevoflurane exposure decreased the expression levels of PPARα in the nuclei of NSPCs and hippocampal tissue. PEA pretreatment increased nuclear PPARα content and CPT1a expression in NSPCs and rat hippocampus after sevoflurane exposure. In addition, pretreatment with PEA or the CPT1a substrate carnitine rescued the sevoflurane-induced decrease in FAO activity in NSPCs, inhibition of neurogenesis in vivo and in vitro and cognitive impairment.
Discussion
Previous work has not investigated whether or how FAO participates in sevoflurane-induced inhibition of neurogenesis and cognitive decline. Our study showed that sevoflurane inhibited neurogenesis and reduced cognitive function likely by inhibiting FAO in NSPCs through the PPARα/CPT1a pathway. This study reveals a new potential mechanism of neurodevelopmental toxicity from sevoflurane. Future research is needed to elucidate the role of FAO in NSPCs in sevoflurane-induced inhibition of neurogenesis and cognitive impairment and to explore the mechanisms that execute this FAO-dependent effect.
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