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miR-182-5p Delivered by Plasma Exosomes Promotes Sevoflurane-Induced Neuroinflammation and Cognitive Dysfunction in
Fu-Sheng Wei1, Mu-Wen Rao1, Yuan-Lu Huang1
1Department of Anesthesiology and Operation, The First Affiliated Hospital of Nanchang University, Nanchang, 330052, Jiangxi, China.
Abstract:
The objective of this study was to discuss the possible mechanism and effect of miR-182-5p delivered by plasma exosomes on sevoflurane-induced neuroinflammation and cognitive disorder in aged rats with postoperative cognitive dysfunction (POCD). Firstly, aged POCD rat models were constructed by sevoflurane anesthesia and superior mesenteric artery occlusion. Subsequently, exosomes and miR-182-5p were inhibited by injection of GW4869 and miR-182-5p-sponge, respectively. Then, exosomes were extracted from the plasma of rats in each group, followed by the determination of the morphology and diameters of exosomes as well as the expression of exosome markers CD63 and CD81 by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. Besides, the Morris water maze (MWM) and fear conditioning test were used to evaluate the learning and memory ability of rats; Western blot to detect the expression levels of neurotrophic factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) as well as NF-κB pathway-related proteins (p65 and p-p65) in rat hippocampal tissues or PC-12 cells; qRT-PCR to assess the expression levels of miR-182-5p and BDNF in rat plasma, plasma exosomes, hippocampal tissues, and PC-12 cells; ELISA to evaluate the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in rat hippocampal tissues; and dual-luciferase reporter assay to verify the targeting relationship between miR-182-5p and BDNF. After examination, the results were obtained as follows. miR-182-5p expression was up-regulated in POCD rats and could be delivered by plasma exosomes. Inhibition of plasma exosomes or miR-182-5p could significantly ameliorate learning and memory disorders; decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β; increase the expression of BDNF and NGF; and inhibit the activity of NF-κB signaling pathway in POCD rat hippocampus. In addition, miR-182-5p could also target and inhibit BDNF. All in all, miR-182-5p delivered by plasma exosomes promotes sevoflurane-induced neuroinflammation and cognitive dysfunction in aged POCD rats by targeting BDNF and activating the NF-κB pathway.
Insights
Plasma exosome-derived miR-182-5p exacerbates sevoflurane-induced cognitive dysfunction in aged rats. Inhibiting miR-182-5p or exosomes improves memory and reduces neuroinflammation by targeting BDNF and the NF-κB pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Gerontology
Background:
- Postoperative cognitive dysfunction (POCD) is a significant concern in aged individuals following anesthesia.
- Sevoflurane anesthesia is implicated in inducing neuroinflammation and cognitive deficits.
- Plasma exosomes are emerging as critical mediators of intercellular communication.
Purpose of the Study:
- To investigate the role of miR-182-5p delivered by plasma exosomes in sevoflurane-induced neuroinflammation and cognitive impairment in aged rats.
- To elucidate the underlying molecular mechanisms involving brain-derived neurotrophic factor (BDNF) and the NF-κB pathway.
Main Methods:
- Construction of aged rat models of POCD using sevoflurane anesthesia.
- Inhibition of plasma exosomes and miR-182-5p using GW4869 and miR-182-5p-sponge, respectively.
- Assessment of cognitive function using Morris water maze and fear conditioning tests.
- Analysis of exosome characteristics, protein expression (BDNF, NGF, NF-κB pathway), cytokine levels (TNF-α, IL-6, IL-1β), and miR-182-5p expression via TEM, NTA, Western blot, qRT-PCR, and ELISA.
- Verification of the miR-182-5p and BDNF targeting relationship using dual-luciferase reporter assay.
Main Results:
- miR-182-5p expression was elevated in POCD rats and transported via plasma exosomes.
- Inhibition of exosomes or miR-182-5p significantly improved learning and memory in rats.
- Treatment reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and inhibited the NF-κB pathway.
- Neurotrophic factors (BDNF, NGF) expression increased, and miR-182-5p was found to directly target and inhibit BDNF.
Conclusions:
- Plasma exosome-mediated delivery of miR-182-5p promotes sevoflurane-induced neuroinflammation and cognitive dysfunction in aged rats.
- miR-182-5p acts by targeting BDNF and activating the NF-κB signaling pathway.
- Targeting miR-182-5p or its exosomal delivery represents a potential therapeutic strategy for POCD.
