Abstract
Mounting evidence has demonstrated that general anesthetics could induce acute neuroapoptosis in developing animals followed by long-term cognitive dysfunction, with the mechanisms remaining largely unknown. The aim of this study was to investigate the effect of the intravenous anesthetic propofol on the profiles of microRNAs (miRNAs) and messenger RNAs (mRNAs), and their interactive signaling networks in the developing mouse hippocampus. Postnatal day 7 (P7) mice were exposed to propofol for 3 hours. Hippocampi were harvested from both P7 (3 hours after exposure) and P60 mice for the analysis of the expression of 726 miRNAs and 24,881 mRNAs, and apoptosis. Long-term memory ability of P60 mice was analyzed using the Morris Water Maze. Propofol induced acute apoptosis in the hippocampus, and impaired memory function of mice. There were 100 altered mRNAs and 18 dysregulated miRNAs in the propofol-treated hippocampi compared with the intralipid-treated control tissues on P7. Bioinformatics analysis of these abnormally expressed genes on P7 indicated that 34 dysregulated miRNA-mRNA target pairs were related to pathological neurological and developmental disorder processes such as cell viability, cell morphology and migration, neural stem cell proliferation and neurogenesis, oligodendrocyte myelination, reactive oxygen species, and calcium signaling. Neonatal propofol exposure also resulted in the abnormal expression of 49 mRNAs and 4 miRNAs in P60 mouse hippocampi. Specifically, bioinformatics analysis indicates that among these dysregulated mRNAs and miRNAs, there were 2 dysregulated miRNA-mRNA targets pairs (Fam46a/miR-363-3p and Rgs3/miR-363-3p) that might be related to the effect of propofol on long-term cognitive function. Collectively, our novel investigation indicates that acute and long-term dysregulated miRNA-mRNA signaling networks potentially participate in propofol-induced developmental neurotoxicity.
Highlights
Mounting evidence from animal studies has shown that various anesthetics exert adverse consequences on developing neuronal cells, resulting in persistent cognitive dysfunction[1,2,3,4]
Propofol exposure for 3 hours induced an increase of cleaved caspase 3 protein expression in the hippocampus of postnatal day 7 (P7) mice compared with mice exposed to the 10% intralipid vehicle control
Morris Water Maze test showed that the time to reach the quadrant where the platform was located was prolonged in the P60 mice receiving neonatal propofol exposure when compared to the intralipid-treated control group (Fig. 1B), suggesting that propofol treatment impaired long-term memory function
Summary
Mounting evidence from animal studies has shown that various anesthetics exert adverse consequences on developing neuronal cells, resulting in persistent cognitive dysfunction[1,2,3,4]. In stem cell-derived human neurons, our group identified that propofol-induced downregulation of miR-21 led to adverse mitochondrial health via the Sprouty 2 protein pathway[22]. Though these data shed some light, the complicated roles of various dysregulated miRNAs underlying propofol-induced neurotoxicity in the developing brain are not fully understood. The aim of this study was to investigate the acute and long-term effects of developmental propofol exposure on miRNA and mRNA profiles in the mouse hippocampus, and to utilize bioinformatic analysis to predict disease pathways, miRNA-mRNA interactions, and the related cellular/molecular events underlying neuronal endpoints (i.e., apoptosis, neurodegeneration, and cognitive function) affected by propofol in order to provide more clues for various mechanisms of the neurotoxic side effects of developmental propofol exposure
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