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Dexmedetomidine suppresses microglial activation in postoperative cognitive dysfunction via the mmu-miRNA-125/TRAF6
Zhiyan Xu1,2, Kaihua Zhong1,2, Weiyuan Chen1,2
1Meizhou People's Hospital (Meizhou Academy of Medical Sciences), Meizhou, China.
Background:
Postoperative cognitive dysfunction (POCD) is driven in part by microglial activation and the resulting neuroinflammatory response. Emerging evidence suggests that microRNAs regulate key inflammatory pathways in the central nervous system. In this study, we examined the role of the mmu‑miR‑125a/TRAF6 signaling axis in microglial activation under inflammatory conditions induced by lipopolysaccharide (LPS) and surgical trauma and evaluated whether dexmedetomidine (DEX) modulates this pathway to alleviate POCD.
Methods:
Murine microglial cells were treated with LPS to induce activation. Expression levels of mmu‑miR‑125a and TRAF6 were quantified by qRT‑PCR and Western blotting. Bioinformatic prediction of miRNA binding sites was performed, and a luciferase reporter assay was used to confirm direct targeting of TRAF6 by mmu‑miR‑125a. Adult mice underwent standardized surgical trauma to induce POCD. Brain tissues were analyzed for microglial activation markers, cytokine levels, and expression of mmu‑miR‑125a and TRAF6. DEX was administered in both in vitro and in vivo models. The effects on cytokine release, microglial activation, and the mmu‑miR‑125a/TRAF6 axis were assessed.
Results:
Our findings revealed significant alterations in the expression levels of TRAF6 and mmu-miR-125a during LPS-induced microglial activation. Through bioinformatics analysis and experimental validation, we identified TRAF6 as a direct target of mmu-miR-125a. The mmu-miR-125a/TRAF6 axis was found to be crucial for regulating microglial activation both in vitro, using an LPS-induced model, and in vivo, using a surgical trauma-induced POCD model. Moreover, we demonstrated that DEX, an alpha-2 adrenergic receptor agonist, effectively modulated the inflammatory cytokine release by targeting the mmu-miR-125a/TRAF6 axis in both models. The administration of DEX significantly suppressed microglial activation and TRAF6 expression, effects that were reversed by the inhibition of mmu-miR-125a.
Conclusion:
Our study provides new insights into the molecular mechanisms underlying microglial activation and highlights the therapeutic potential of targeting the mmu-miR-125a/TRAF6 axis to alleviate neuroinflammation by the administration of DEX in POCD.
Insights
This study reveals that the mmu-miR-125a/TRAF6 pathway drives neuroinflammation in postoperative cognitive dysfunction (POCD). Dexmedetomidine (DEX) alleviates POCD by targeting this pathway, offering therapeutic potential.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Postoperative cognitive dysfunction (POCD) is linked to microglial activation and neuroinflammation.
- MicroRNAs are emerging regulators of central nervous system inflammatory pathways.
- The mmu-miR-125a/TRAF6 signaling axis is implicated in microglial activation.
Purpose of the Study:
- To investigate the role of the mmu-miR-125a/TRAF6 axis in microglial activation.
- To determine if dexmedetomidine (DEX) modulates this axis to alleviate POCD.
- To elucidate the molecular mechanisms of DEX in treating neuroinflammation.
Main Methods:
- Utilized lipopolysaccharide (LPS) to induce microglial activation in vitro.
- Employed qRT-PCR and Western blotting to quantify gene and protein expression.
- Confirmed direct targeting of TRAF6 by mmu-miR-125a using bioinformatics and luciferase assays.
- Induced POCD in mice via surgical trauma and assessed molecular changes.
- Administered DEX in vitro and in vivo to evaluate its effects on the mmu-miR-125a/TRAF6 axis and inflammation.
Main Results:
- Identified significant alterations in mmu-miR-125a and TRAF6 expression during LPS-induced microglial activation.
- Validated TRAF6 as a direct target of mmu-miR-125a.
- Demonstrated the crucial role of the mmu-miR-125a/TRAF6 axis in regulating microglial activation in both in vitro and in vivo POCD models.
- Showed that DEX effectively modulated inflammatory cytokine release by targeting this axis.
- Observed that DEX suppressed microglial activation and TRAF6 expression, with effects reversed by mmu-miR-125a inhibition.
Conclusions:
- The mmu-miR-125a/TRAF6 axis is a key regulator of microglial activation and neuroinflammation in POCD.
- Dexmedetomidine (DEX) shows therapeutic potential for POCD by targeting the mmu-miR-125a/TRAF6 pathway.
- This study provides novel insights into the molecular mechanisms underlying POCD and neuroinflammation.
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