MicroRNA-96 is responsible for sevoflurane-induced cognitive dysfunction in neonatal rats via inhibiting IGF1R

Abstract

Sevoflurane is an experimental potent yet volatile anesthesia agent characterized by a low blood/gas partition coefficient. However, exposure to sevoflurane in neonatal mice has been speculated to result in learning deficits and abnormal social behavior. The aim of the present study was to investigate the relationship between sevoflurane and miR-96, in an attempt to identify the means by which it mediates IGF1R to influence the cognitive dysfunction (CD) in neonatal rats. Relationship between differentially expressed miRNAs and sevoflurane concentration was identified. The potential underlying regulatory mechanisms involved with sevoflurane were investigated through the administration of varying concentrations of the agent (1%, 2% and 4%), combined with miR-96 mimic or an inhibitor. A target prediction program was utilized, while the luciferase activity was determined in order to verify whether miR-96 targets IGF1R. The mRNA and protein levels of IGF1R, Bcl-2, Bax, and caspase-3 were measured followed by the determination of hippocampal neuron apoptosis. Learning and memory performance was assessed using the Morris water maze (MWM) test and step-down test. The obtained results highlighted a positive correlation between miR-96 and the concentration of sevoflurane, while miR-96 was confirmed to negatively target IGF1R. Our analyses indicated that 4% sevoflurane had a significantly stronger effect on reducing the levels of IGF1R and Bcl-2, while elevating the levels of miR-96, Bax and caspase-3 more so than that of 1% or 2% sevoflurane, which resulted in increased hippocampal neuron apoptosis but diminished the learning and memory performance of the rats. The addition of miR-96 mimic was demonstrated to exacerbate the influence of sevoflurane on hippocampal neurons as well as the cognitive function of the rats. The key findings of our study highlighted the role of miR-96 in the potential mechanism of sevoflurane anesthesia-induced CD in neonatal rats through the downregulation of IGF1R.

Keywords: Apoptosis; Cognitive dysfunction; Hippocampal neuron; IGF1R; MicroRNA-96; Sevoflurane.