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Sevoflurane impairs neurogenesis and cognitive function by inhibiting fatty acid β-oxidation in neural stem/progenitor cells of neonatal rats

Jia Pengyu,Wang Kui,Cheng Yiqin,Zhang Yan,Lu Yuying,Sun Haodong,Zhang Shuyue,Fan Pei,Zhang Yuanyuan,Yang Liufei,Wang Ning,Lu Haixia,Chen Xinlin,Liu Yong,Wei Haidong,Zhang Pengbo

Plain Language Summary Background: Sevoflurane impairs neurogenesis and cognitive function in the developing brain; however, the underlying mechanisms remain unclear. This study aimed to investigate the role of fatty acid β-oxidation (FAO) in neural stem/progenitor cells (NSPCs) as a potential factor in sevoflurane-induced neurogenesis inhibition and cognitive deficits. Methods: NSPCs, NE-4C cells, and postnatal day 7 (PND 7) rats were exposed to sevoflurane. Cell viability was measured using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Neurogenesis was assessed by immunohistochemistry. Apoptosis was detected via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Cognitive function was tested with the Morris water maze. Lipid metabolism profiles were analyzed through lipidomics. Message RNA (mRNA) expression levels of key FAO enzymes and the major carnitine transporter were quantified by real-time reverse transcription polymerase chain reaction (RT-qPCR). Protein expression of carnitine palmitoyltransferase 1a (CPT1a) and nuclear peroxisome proliferator-activated receptor α (PPARα) was examined by Western blotting. CPT1a enzymatic activity was determined using a biochemical assay. FAO activity was measured with the FAOBlue assay. Results: Sevoflurane exposure impaired neurogenesis and cognitive function. In NSPCs, sevoflurane exposure induced extensive alterations 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, reduced CPT1a expression and activity, and decreased PPARα levels in the nucleus. Enhancing FAO activity in NSPCs ameliorated the negative effects of sevoflurane on neurogenesis. Overexpression of CPT1a rescued the sevoflurane-induced inhibition of FAO activity and neurogenesis in NE-4C cells. Pretreatment with palmitoylethanolamide (PEA), a PPAPα agonist, increased both the nuclear content of PPARα protein and the expression of CPT1a in NSPCs and rat hippocampus after sevoflurane exposure. Furthermore, pretreatment with PEA or the CPT1a substrate carnitine rescued sevoflurane-induced damage to FAO activity in NSPCs, neurogenesis, and cognitive function. Conclusion: Sevoflurane impairs neurogenesis and cognitive function by suppressing FAO in NSPCs of the developing brain. Boosting FAO activity in NSPCs could be a potential strategy to prevent sevoflurane-induced cognitive deficits. Plain Language Summary This study explored how sevoflurane, an anesthetic, affects brain development by impairing neurogenesis and cognitive function. Researchers found that sevoflurane disrupts fatty acid β-oxidation (FAO) in neural stem/progenitor cells (NSPCs), leading to changes in lipid metabolism and reduced expression of key enzymes. Enhancing FAO activity, either by overexpressing certain proteins or using compounds like palmitoylethanolamide (PEA) and carnitine, helped mitigate these negative effects. This suggests that targeting FAO in NSPCs could be a promising approach to counteract sevoflurane-induced cognitive deficits in the developing brain. Text is machine generated and may contain inaccuracies. FAQ