Neonatal administration of a subanaesthetic dose of JM-1232(\u2212) in mice results in no behavioural deficits in adulthood

Koji Iwanaga,Tomiei Kazama,Toshiaki Ishizuka,Yasushi Satoh,Ryosuke Akai,Takehiko Ikeda

doi:10.1038/s41598-021-92344-3

Koji Iwanaga, Tomiei Kazama + Show 4 more

Open Access

https://doi.org/10.1038/s41598-021-92344-3

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Abstract

In animal models, neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood. Consequently, there is growing concern about the use of general anaesthetics in obstetric and paediatric practice. JM-1232(−) has been developed as a novel intravenous anaesthetic, but the effects of JM-1232(−) on the developing brain are not understood. Here we show that neonatal administration of JM-1232(−) does not lead to detectable behavioural deficits in adulthood, contrarily to other widely-used intravenous anaesthetics. At postnatal day 6 (P6), mice were injected intraperitoneally with a sedative-equivalent dose of JM-1232(−), propofol, or midazolam. Western blot analysis of forebrain extracts using cleaved poly-(adenosine diphosphate-ribose) polymerase antibody showed that JM-1232(−) is accompanied by slight but measurable apoptosis 6 h after administration, but it was relatively small compared to those of propofol and midazolam. Behavioural studies were performed in adulthood, long after the neonatal anaesthesia, to evaluate the long-term effects on cognitive, social, and affective functions. P6 administration to JM-1232(−) was not accompanied by detectable long-term behavioural deficits in adulthood. However, animals receiving propofol or midazolam had impaired social and/or cognitive functions. These data suggest that JM-1232(−) has prospects for use in obstetric and paediatric practice.

Highlights

In animal models, neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood
To estimate an ED50 value of JM-1232(−) in mice at postnatal day 6 (P6), we evaluated the dose-dependent sedative effect using the loss of righting reflex (LORR) test
Extrapolating from animal models to humans can be fraught with difficulties, results from animals suggest that repeated or lengthy use of general anaesthetic during surgery in children younger than 3 years may affect brain development, which can be manifested later in adulthood as cognitive problems

Summary

Introduction

Neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood. Accumulating evidence indicates that exposure to general anaesthetics at clinically relevant concentrations induces a widespread increase in neuronal apoptosis in the developing brain of a variety of animals, from rodents to rhesus m onkeys[1,2,3,4,5,6,7,8,9,10,11]. We sought to determine the short- and long-term effects of JM-1232(−) on the developing mouse brain and compare those effects with those of propofol and midazolam

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