Neonatal sevoflurane exposure disrupted fatty acids metabolism, leading to hypomyelination and neurological impairments

Myelin is a lipid-rich substance that is crucial for neural function. Neonatal anesthesia has been linked to neurological impairments associated with myelination dysfunction. This study sought to evaluate whether disrupted fatty acid homeostasis is involved in the mechanism of sevoflurane developmental neurotoxicity. Sevoflurane (3 %, 2 h/day) was administered to mice from postnatal day (P) P6 to P8. Subsequently, ultra-performance liquid chromatography and RNA sequencing (RNA-seq) were used to investigate the effects of sevoflurane on long-chain fatty acid metabolism at P9. Behavioral tests and myelination development were analyzed at P50. Peroxisome proliferator-activated receptor β (PPARβ) agonist administration and docosahexaenoic acid (DHA) treatment were performed to assess their rescuing effect on sevoflurane-impaired cognition in the mice. Following neonatal exposure to sevoflurane, a number of differentially expressed genes (DEGs) were closely related to lipid metabolism. Lipidomic analysis demonstrated that concentrations of long-chain fatty acids were dramatically reduced by repeated sevoflurane exposure. Consistently, cognitive impairments and hypomyelination were observed. Furthermore, the PPARβ agonist KD3010 attenuated the adverse effects of sevoflurane exposure on cognitive function and myelination. DHA treatment mimicked the protective effects of KD3010. These data demonstrate that repeated neonatal sevoflurane exposures result in profound changes in long-chain fatty acids metabolism, hypomyelination and subsequently, neurological impairments. Sevoflurane-induced myelin impairment is associated with changes in fatty acid content and composition, which may be mediated by the PPARβ pathway. These findings highlight the pivotal role of long-chain fatty acids in neonatal sevoflurane-associated neurotoxicity and open a new window for developing therapeutic strategies for sevoflurane-associated neurodevelopmental impairments.