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A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
Microglial exosome miR-124-3p in hippocampus alleviates cognitive impairment induced by postoperative pain in elderly
Erliang Kong1, Xuqiang Geng2, Feixiang Wu3
1Department of Anesthesiology, The 988th Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Zhengzhou, China.
Abstract:
Cognitive impairment induced by postoperative pain severely deteriorates the rehabilitation outcomes in elderly patients. The present study focused on the relationship between microglial exosome miR-124-3p in hippocampus and cognitive impairment induced by postoperative pain. Cognitive impairment model induced by postoperative pain was constructed by intramedullary nail fixation after tibial fracture. Morphine intraperitoneally was carried out for postoperative analgesia. Morris water maze tests were carried out to evaluate the cognitive impairment, while mRNA levels of neurotrophic factors (BDNF, NG) and neurodegenerative biomarker (VILIP-1) in hippocampus were tested by q-PCR. Transmission electron microscope was used to observe the axon degeneration in hippocampus. The levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6), the levels of anti-inflammatory factors (Ym, Arg-1, IL-10) and microglia proliferation marker cyclin D1 in hippocampus were measured to evaluate microglia polarization. Bioinformatics analysis was conducted to identify key exosomes while BV-2 microglia overexpressing exosome miR-124-3p was constructed to observe microglia polarization in vitro experiments. Exogenous miR-124-3p-loaded exosomes were injected into hippocampus in vivo. Postoperative pain induced by intramedullary fixation after tibial fracture was confirmed by decreased mechanical and thermal pain thresholds. Postoperative pain induced cognitive impairment, promoted axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus. Postoperative pain also increased pro-inflammatory factors, cyclin D1 and decreased anti-inflammatory factors in hippocampus. However, these changes were all reversed by morphine analgesia. Bioinformatics analysis identified the critical role of exosome miR-124-3p in cognitive impairment, which was confirmed to be down-regulated in hippocampus of postoperative pain mice. BV-2 microglia overexpressing exosome miR-124-3p showed decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. In vivo, stereotactic injection of exogenous miR-124-3p into hippocampus decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. The cognitive impairment, axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus were all alleviated by exogenous exosome miR-124-3p. Microglial exosome miR-124-3p in hippocampus alleviates cognitive impairment induced by postoperative pain through microglia polarization in elderly mice.
Insights
Postoperative pain in elderly mice causes cognitive impairment by altering microglial exosome miR-124-3p. Restoring miR-124-3p levels alleviates this impairment and neuroinflammation.
Area of Science:
- Neuroscience
- Gerontology
- Molecular Biology
Background:
- Postoperative pain in elderly patients leads to cognitive impairment, hindering rehabilitation.
- Microglial exosomes and their microRNA (miRNA) cargo are implicated in neuroinflammation and cognitive function.
Purpose of the Study:
- To investigate the role of microglial exosome miR-124-3p in the hippocampus concerning cognitive impairment induced by postoperative pain in elderly mice.
- To explore the therapeutic potential of modulating exosome miR-124-3p for postoperative cognitive dysfunction.
Main Methods:
- A mouse model of postoperative pain was established using tibial fracture fixation.
- Cognitive function was assessed using Morris water maze tests.
- Hippocampal gene and protein expression (neurotrophic factors, neuroinflammation markers, microglia polarization markers) were analyzed using qPCR and other techniques.
- In vitro and in vivo experiments involved manipulating exosome miR-124-3p levels in microglia and the hippocampus.
Main Results:
- Postoperative pain induced cognitive impairment, axon demyelination, altered neurotrophic factor and neurodegenerative biomarker expression, and promoted pro-inflammatory microglia polarization.
- Morphine analgesia reversed these detrimental effects.
- Exosome miR-124-3p was found to be downregulated in the hippocampus following postoperative pain.
- Overexpression of miR-124-3p in microglia and direct hippocampal injection of miR-124-3p-loaded exosomes alleviated cognitive impairment and neuroinflammation.
Conclusions:
- Microglial exosome miR-124-3p plays a critical role in mediating cognitive impairment associated with postoperative pain in elderly mice.
- Restoring hippocampal exosome miR-124-3p levels can ameliorate cognitive deficits and neuroinflammation, suggesting a potential therapeutic target.
