Date Published: December 12, 2018
Publisher: Impact Journals
Author(s): Xin Zhao, Yanwu Jin, Haibo Li, Yuxiu Jia, Yuelan Wang.
The molecular mechanisms underlying sevoflurane (SEVO)-induced impairment of learning and memory remain unclear. Specifically, a role of microRNAs (miRNAs) in the control of the neuron proliferation in the developing brain exposed to SEVO has not been reported previously. Here, we studied the effects of SEVO exposure on the neural cell proliferation, and on the learning and memory of neonatal rats. We found that SEVO exposure significantly decreased neuron cell proliferation, reduced BDNF levels in brain, and impaired learning and memory of neonatal rats in Morris water maze test and Plus-Maze discriminative avoidance task (PM-DAT), likely through downregulation of CCNA2 protein. Next, we used bioinformatic tools to predict CCNA2-binding microRNAs (miRNAs), and found that miR-19-3p was upregulated in neurons exposed to SEVO. Moreover, miR-19-3p functionally inhibited the protein translation of CCNA2 in a human neural cell line, HCN-2. Furthermore, intracranial injection of adeno-associated virus carrying antisense of miR-19-3p under a CMV promoter into the neonatal rats significantly alleviated SEVO exposure-induced impairment of neuron cell proliferation, as well as the learning and memory of the rats. Together, our data suggest that SEVO-induced upregulation of miR-19-3p post-transcriptionally inhibits CCNA2, which contributes to the SEVO-associated impairment of learning and memory of the neonatal rats.
Whether sevoflurane (SEVO) may affect developing brain and cause learning and memory impairment is still under debate. Some studies have shown that SEVO are toxic to neuron cells in the developing brain, resulting in long-term deficits in neurocognition and learning ability [1–7], while others have disagreed with at least parts of these conclusions [8–11]. The discrepancy largely results from the insufficient understanding of the molecular mechanisms underlying the experimental observed phenotype.
Accumulating evidence have particularly shown that SEVO exposure may have non-negligible effects on the developing brain in either embryonic stage [1,4,19,20] or neonatal period [2,3,5,7,21–24]. Although different mechanisms have been proposed for the early-age-exposure-to-SEVO-induced impairment of the learning and memory ability, none of the previous studies has focused on the alteration of proliferation potential of neurons.