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Neonatal exposure to sevoflurane may not cause learning and memory deficits and behavioral abnormality in the childhood of Cynomolgus monkeys.

ABSTRACT: Results of animal studies have raised a significant concern that commonly used general anesthetics may induce neurotoxicity in children. It may be difficult to resolve this concern with human studies because randomizing children only for testing anesthetic toxicity may not be feasible. We randomized 6-day old male Cynomolgus monkeys to receive or not to receive sevoflurane anesthesia at surgical plane for 5 h. Sevoflurane is the most commonly used general anesthetic in children in the U.S.A. Here, we showed that sevoflurane anesthesia did not affect the behavior evaluated by holding cage method when the monkeys were 3 and 7 months old. However, there was an age-dependent decrease in the frequency of stress events and environmental exploration behavior during the test. Sevoflurane also did not affect the learning and memory of the monkeys when they were assessed from the age of 7 months. Finally, sevoflurane did not affect the expression of multiple neuron-specific proteins in the hippocampus and cerebral cortex of 10-month old monkeys after all behavioral and cognitive tests were completed. These results suggest that exposure of neonatal monkey to sevoflurane may not affect cognition, behavior and neuronal structures in childhood, indicating the safety of sevoflurane anesthesia in children.

SUBMITTER: Zhou L

PROVIDER: S-EPMC4457164 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description: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.

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Neonatal exposure to sevoflurane may not cause learning and memory deficits and behavioral abnormality in the childhood of Cynomolgus monkeys.

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