Propofol Induces Apoptosis of Neurons but Not Astrocytes, Oligodendrocytes, or Neural Stem Cells in the Neonatal Mouse Hippocampus

Yasheng Yan,Thiago Arzua,Chika Kikuchi,Sarah Logan,Xiaowen Bai,Shigang Qiao,Ivan Zaja,Congshan Jiang

doi:10.3390/brainsci7100130

Yasheng Yan, Thiago Arzua + Show 6 more

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https://doi.org/10.3390/brainsci7100130

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Abstract

It has been shown that propofol can induce widespread apoptosis in neonatal mouse brains followed by long-term cognitive dysfunction. However, selective brain area and cell vulnerability to propofol remains unknown. This study was aimed to dissect toxic effect of propofol on multiple brain cells, including neurons, astrocytes, oligodendrocytes, and neural stem cells (NSCs). Seven-day-old mice were intraperitoneally administrated propofol or intralipid as a vehicle control for 6 hours. To identify vulnerable cells undergoing apoptosis following propofol exposure, brain sagittal sections were co-stained with antibodies against an apoptosis marker along with neuron, astrocyte, oligodendrocyte, or NSC markers using immunofluorescence staining. The results showed widespread apoptosis in propofol-treated brains (apoptotic cells: 1.55 ± 0.04% and 0.06 ± 0.01% in propofol group and intralipid-treated control group, respectively). Apoptotic cell distribution exhibits region- and cell-specific patterns. Several brain regions (e.g., cerebral cortex and hippocampus) were more vulnerable to propofol than other brain regions. Most apoptotic cells in the hippocampus were located in the cornus ammonis 1 (CA1) subfield. These apoptotic cells were only detected in neurons and not astrocytes, oligodendrocytes, or NSCs. These data demonstrate that different brain regions, subfields, and different types of neuronal cells in mice exhibit various vulnerabilities to propofol. Understanding region- and cell-specific susceptibility to propofol will help to better understand cellular contribution to developmental neurotoxicity and further develop novel therapeutic targets.

Highlights

Propofol, a short-acting agent with rapid induction and recovery times, is one of the most widely used general intravenous anesthetics in pediatrics and obstetrics [1]
Since hippocampus is a brain region primarily associated with memory and learning, and our pilot experiments indicated that most of the apoptotic cells were observed in the cornus ammonis 1 (CA1) subfield of the hippocampus, we confined the quantitative assessment of vulnerable neuronal cells to CA1 following immunofluorescence staining as described above
Based on the evaluation of the density and distribution of activated caspase 3–positive apoptotic signals, we found that several brain regions such as the cerebral cortex, caudate/putamen, thalamus, hippocampus, subiculum and entorhinal cortex, inferior colliculus, and cerebellum, were more vulnerable to propofol than other regions

Summary

Introduction

A short-acting agent with rapid induction and recovery times, is one of the most widely used general intravenous anesthetics in pediatrics and obstetrics [1]. Growing evidence suggests that exposure of propofol at clinically relevant doses and durations to developing animals (including both rodents and primates) during brain growth spurt causes widespread neuronal cell death followed by long-term memory and learning abnormalities, as observed in other anesthetic (e.g., isoflurane, ketamine, and sevoflurane) neurotoxicity studies [2,3,4,5,6,7]. This brain growth spurt period ranges differently among species. The neurotoxicity effect was observed in developing non-human primate (NHP) rhesus macaque brains [4]

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