Abstract
Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects post-surgery patients. Sevoflurane anesthesia is linked to cognitive dysfunction correlated to the expression of miRNA levels. In the current study, we investigated if miR-124 can offer protection against cognitive deficits induced by sevoflurane in a spatial learning paradigm, and examined the molecular mechanisms through cell cultures. Escape latency, platform crossings in probe trials and swimming speed in the Morris water maze in sevoflurane-treated mice were utilized as a measure of cognitive function. The relative miR-124 expression, and mRNA expressions of Bax, caspase-3 and Bcl-2 in sevoflurane-treated hippocampal cultures were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, the changes in interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α) and IL-6 were determined using enzyme-linked immunosorbent assay (ELISA). The binding between miR-124 and calpain small subunit 1 (Capn4) was verified with site-directed mutagenesis. The involvement of the nuclear factor kappa B (NF-κB) signaling pathway was examined using western blot analysis. Our findings indicated that the miR-124 expression was inhibited by sevoflurane treatment in live rats and mouse hippocampal neurons to prevent apoptosis and inflammatory responses. We confirmed Capn4 as a target of miR-124. Treatment with sevoflurane enhanced the expression of Capn4, while overexpression of miR124 suppressed the enhanced expression of Capn4. Also, miR-124 inhibited apoptosis in murine hippocampal neurons induced by sevoflurane via the NF-κB signaling pathway. Our findings demonstrated that miR-124 exerted its neuroprotective role against sevoflurane via targeting Capn4 and NF-κB signaling pathways. Our work may provide a novel and efficacious treatment for sevoflurane anesthesia-related cognitive dysfunction.
Highlights
Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects postsurgery patients
Our findings indicated that the miR-124 expression was inhibited by sevoflurane treatment in live rats and mouse hippocampal neurons to prevent apoptosis and inflammatory responses
Our findings demonstrated that miR-124 exerted its neuroprotective role against sevoflurane via targeting Capn[4] and NF-κB signaling pathways
Summary
Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects postsurgery patients. MiR-134 overexpression decreases the size of dendritic spines in the hippocampus.[10,11,12] miR-124 plays a vital role in the regulation of synaptic facilitation induced by serotonin at the sensory-motor synapse, and the overexpression of miR-124 reduced the expression of CREB, which is a gene related to synaptic plasticity.[13] Emerging evidence suggests that miR-9, miR-124 and miR-29a/b-1 are dysregulated and enhanced the production of Aβ in the brains of patients with Alzheimer’s disease (AD).[14,15] MiR-124 is preferentially expressed in the central nervous system (CNS), up to 100-fold in neurons compared to other organs in the rat.[16] It was found to regulate cholinergic anti-inflammatory action via decreasing the release of inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6.17 It acted as an anti-apoptotic regulator and exerted its neuroprotective effect towards ischemic injury by suppressing the apoptosis of neurons in the cerebral ischemic stroke.[18] the role of miR-124 on sevoflurane anesthesia-induced cognitive dysfunction has not been elucidated
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