Multiple
sevoflurane exposure may result in cognitive deficits in neonatal animals. This study attempted to investigate the potential mechanism of
sevoflurane-induced neurotoxicity in developing hippocampus. Neonatal animals received
sevoflurane anesthesia, then the behavioral tests and Golgi-Cox staining were employed to detect the effect of
sevoflurane inhalation in adult mice. And the mitochondrial function was evaluated using
MitoSOX staining, Fluo
calcium indicators,
mitochondrial permeability transition pore (mPTP) assay, and
JC-1 probe after
sevoflurane administration. Meanwhile, mitochondrial
lipid hydroperoxide and ferroptosis were measured by MitoPeDPP and Mito-FerroGreen signals following
sevoflurane exposure. Moreover, the ferroptosis and behavioral performance were assessed after
deferiprone (
DFP) treatment. The results showed that
sevoflurane administration induced
cognitive impairment accompanied by reducing dendritic length, density, and nodes. Additionally,
sevoflurane exposure elevated mitochondrial ROS production and cytoplasm
calcium levels, triggered the opening of
mPTP, and decreased the mitochondrial membrane potential (
MMP). However, supplement of
elamipretide (SS-31) effectively reversed
mitochondrial dysfunction. Mitochondrial
lipid hydroperoxide production was increased after
sevoflurane administration, whereas Fer-1 treatment reduced
lipid hydroperoxide formation.
Sevoflurane exposure induced mitochondrial
iron overload, whereas Mito-
Tempo treatment reduced
iron accumulation.
Prussian blue staining showed that the hippocampal
iron deposition was apparently increased after
sevoflurane inhalation. Additionally, the ferroptosis-related
protein expression (including ACSL4, COX2, GPX4, and FTH1) was significantly changed, whereas
DFP effectively suppressed ferroptosis and enhanced
sevoflurane-induced behavioral malfunction. These findings demonstrated that
sevoflurane administration elicited
mitochondrial dysfunction and
iron dyshomeostasis and eventually resulted in
cognitive impairments, whereas protecting mitochondrial function and chelating neurotoxic
iron effectively reversed these
pathological processes.