MiR-124 protects against cognitive dysfunction induced by sevoflurane anesthesia in vivo and in vitro through targeting calpain small subunit 1 via NF-κB signaling pathway

Abstract

Background. Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects postsurgery patients. Sevoflurane anesthesia is linked to cognitive dysfunction correlated to the expression of miRNA levels.Objectives. 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.Materials and methods. 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. Results.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. Conclusions.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.

Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction

“…Recently, Li et al (2022b) found that up-regulation of miR-424 attenuated sevoflurane-induced NF-κB phosphorylation, and up-regulation of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) was achieved by targeting the 3’-untranslated region of TLR4 and inducing mRNA degradation ( Li et al, 2022b ). In addition, Zhao et al (2021) found that miR-124 inhibited sevoflurane-induced apoptosis of mouse hippocampal neurons by targeting Capn4 and suppressing NF-κB signaling pathway ( Zhao et al, 2021 ). In contrast, circ-001372 contributed to the improvement of anesthetics-related cognitive disorders by inhibiting the NF-κB signaling pathway ( Wang et al, 2021a ).…”

MicroRNA-424-5p Alleviates Isoflurane Anesthesia-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons by Targeting FASN

“…Downregulation of miR-106a alleviates the cognition-related impairments of mice subjected to ISO treatment [ 18 ]. miR-124 is confirmed to protect against sevoflurane-induced cognitive dysfunction via targeting the Capn4/NF- κ B signaling [ 19 ]. Recently, miRNAs have presented potential influence on the regulation of neuronal injury induced by ISO.…”

IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway

“…NF-κB is able to regulate the expression of cytokines and modulate the immune system [ 44 ]. Several studies [ 43 , 45 ] and our previous report [ 46 ] suggested that the NF-κB signaling pathway plays a pivotal role in the sevoflurane-induced neuroinflammatory response. iNOS is a pro-inflammatory enzyme that produces NO.…”