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Background <p>Traumatic brain injury (TBI) remains a major public health concern worldwide. With wide clinical demands, therapies for TBI are far from satisfactory. Dexmedetomidine (DEX) exhibits neuroprotective effects on multiple neurological disorders, which may present a viable therapeutic opportunity in TBI.</p> Objective <p>To investigate the mechanism of (Dex) in repairing behavioral deficits in a mouse model of TBI.</p> Methods <p>This study investigated the potential role of Dex in cerebral TBI using controlled cortical impact (CCI)-injured mice and stretch-damaged HT22 cells. Behavioral tests were used to observe the behavioral changes of mice, the brain edema of mice was measured, and the permeability of blood–brain barrier was detected by Evans blue. Nissl staining was used to observe the morphology of neurons in the hippocampus of the injured brain tissue of mice, and TUNEL staining was used to evaluate the apoptosis of neurons. The effects of Dex on HT22 cells were evaluated by CCK-8, LDH release assay and flow cytometry. Oxidative stress injury-related indicators SOD, GSH-Px, and MDA in brain tissue and cell supernatant were measured. miR-365a-3p and G3BP2 were detected by RT-qPCR, and G3BP2, Bax, Bcl-2 and Nrf2/Keap1 signaling pathway-related proteins were detected by Western blot. Bioinformatics analysis and luciferase reporter assay were used to verify the targeting relationship between miR-365a-3p and G3BP2.</p> Results <p>Dex effectively repaired behavioral deficits and improved brain edema, BBB permeability, neuronal apoptosis, and oxidative stress injury in TBI mice in a dose-dependent manner. Dex intervention significantly elevated cell viability and inhibited cytotoxicity, apoptosis and oxidative stress injury in cell injury model. miR-365a-3p was up-regulated by Dex, and miR-365a-3p targeted G3BP2. Silencing miR-365a-3p or overexpressing G3BP2 weakened protective effect of Dex on stretch-induced injury in HT22 cells. Dex activated the Nrf2/Keap1 pathway by mediating the miR-365a-3p/G3BP2 axis.</p> Conclusion <p>Dex effectively repairs behavioral deficits in TBI mice, and its effects are associated with the up-regulation of miR-365a-3p to inhibit G3BP2 and regulate the Nrf2/Keap1 pathway.</p>

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Dexmedetomidine repairs behavioral deficits through miR-365a-3p/G3BP2 axis and Nrf2/Keap1 signaling pathway in traumatic brain injury

  • 期刊论文

  • 发表日期：

    2025年3月18日

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  • PeiPei Kang,
  • YuanLi Gao,
  • JuYan Zheng,
  • JiaQin Chen,
  • ZhiYun Li,
  • GuJun Cong

摘要

Background

Traumatic brain injury (TBI) remains a major public health concern worldwide. With wide clinical demands, therapies for TBI are far from satisfactory. Dexmedetomidine (DEX) exhibits neuroprotective effects on multiple neurological disorders, which may present a viable therapeutic opportunity in TBI.

Objective

To investigate the mechanism of (Dex) in repairing behavioral deficits in a mouse model of TBI.

Methods

This study investigated the potential role of Dex in cerebral TBI using controlled cortical impact (CCI)-injured mice and stretch-damaged HT22 cells. Behavioral tests were used to observe the behavioral changes of mice, the brain edema of mice was measured, and the permeability of blood–brain barrier was detected by Evans blue. Nissl staining was used to observe the morphology of neurons in the hippocampus of the injured brain tissue of mice, and TUNEL staining was used to evaluate the apoptosis of neurons. The effects of Dex on HT22 cells were evaluated by CCK-8, LDH release assay and flow cytometry. Oxidative stress injury-related indicators SOD, GSH-Px, and MDA in brain tissue and cell supernatant were measured. miR-365a-3p and G3BP2 were detected by RT-qPCR, and G3BP2, Bax, Bcl-2 and Nrf2/Keap1 signaling pathway-related proteins were detected by Western blot. Bioinformatics analysis and luciferase reporter assay were used to verify the targeting relationship between miR-365a-3p and G3BP2.

Results

Dex effectively repaired behavioral deficits and improved brain edema, BBB permeability, neuronal apoptosis, and oxidative stress injury in TBI mice in a dose-dependent manner. Dex intervention significantly elevated cell viability and inhibited cytotoxicity, apoptosis and oxidative stress injury in cell injury model. miR-365a-3p was up-regulated by Dex, and miR-365a-3p targeted G3BP2. Silencing miR-365a-3p or overexpressing G3BP2 weakened protective effect of Dex on stretch-induced injury in HT22 cells. Dex activated the Nrf2/Keap1 pathway by mediating the miR-365a-3p/G3BP2 axis.

Conclusion

Dex effectively repairs behavioral deficits in TBI mice, and its effects are associated with the up-regulation of miR-365a-3p to inhibit G3BP2 and regulate the Nrf2/Keap1 pathway.