Multiple sevoflurane exposures during mid-trimester induce neurotoxicity in the developing brain initiated by 15LO2-Mediated ferroptosis

Abstract

Aims: Mid-gestational sevoflurane exposure may induce notable long-term neurocognitive impairment in offspring. This study was designed to investigate the role and potential mechanism of ferroptosis in developmental neurotoxicity induced by sevoflurane in the second trimester. Methods: Pregnant rats on day 13 of gestation (G13) were treated with or without 3.0% sevoflurane, Ferrostatin-1 (Fer-1), PD146176, or Ku55933 on three consecutive days. Mitochondrial morphology, ferroptosis-relative proteins, malondialdehyde (MDA) levels, total iron content, and glutathione peroxidase 4 (GPX4) activities were measured. Hippocampal neuronal development in offspring was also examined. Subsequently, 15-lipoxygenase 2 (15LO2)-phosphatidylethanolamine binding protein 1 (PEBP1) interaction and expression of Ataxia telangiectasia mutated (ATM) and its downstream proteins were also detected. Furthermore, Morris water maze (MWM) and Nissl's staining were applied to estimate the long-term neurotoxic effects of sevoflurane. Results: Ferroptosis mitochondria were observed after maternal sevoflurane exposures. Sevoflurane elevated MDA and iron levels while inhibiting GPX4 activity, and resultant long-term learning and memory dysfunction, which were alleviated by Fer-1, PD146176, and Ku55933. Sevoflurane could enhance 15LO2-PEBP1 interaction and activate ATM and its downstream P53/SAT1 pathway, which might be attributed to excessive p-ATM nuclear translocation. Conclusion: This study proposes that 15LO2-mediated ferroptosis might contribute to neurotoxicity induced by maternal sevoflurane anesthesia during the mid-trimester in the offspring and its mechanism may be ascribed to hyperactivation of ATM and enhancement of 15LO2-PEBP1 interaction, indicating a potential therapeutic target for ameliorating sevoflurane-induced neurotoxicity.