Dexmedetomidine alleviates sevoflurane-induced cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway

CHEN Ying; YANG Mei; YANG Yishan; WANG Hong; REN Liwen; HAN Xu; TANG Songjiang

doi:10.16016/j.2097-0927.202509053

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Dexmedetomidine alleviates sevoflurane-induced cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway

Neuroscience | 更新时间：2025-12-30

- Dexmedetomidine alleviates sevoflurane-induced cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway
- Journal of Army Medical University Vol. 47, Issue 24, Pages: 3077-3088(2025)
- 作者机构：
  
  贵州中医药大学第一附属医院麻醉科，贵州贵阳
- 作者简介：
  
  TANG Songjiang，E-mail： 214459348@qq.com
- 基金信息：
  
  the Project of Science and Technology Fund of Guizhou Provincial Health Commission(gzwkj2022-485);the College-level Project of Nursing College of Guizhou University of Traditional Chinese Medicine(HL2509002)
- DOI：10.16016/j.2097-0927.202509053
  CLC： R741;R971.2;R971.3
- Received：15 September 2025，
  
  Revised：2025-12-03，
  
  Published：30 December 2025
- 稿件说明：
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陈英，杨梅，杨义姗，等.右美托咪定通过抑制mTOR/NF-κB信号通路减轻七氟烷诱导的新生大鼠认知功能障碍［J］.陆军军医大学学报，2025，47（24）：3077-3088.DOI：10.16016/j.2097-0927.202509053.

CHEN Y，YANG M，YANG Y H，et al.Dexmedetomidine alleviates sevoflurane-induced cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway［J］.J Army Med Univ，2025，47（24）：3077-3088.DOI：10.16016/j.2097-0927.202509053.
陈英，杨梅，杨义姗，等.右美托咪定通过抑制mTOR/NF-κB信号通路减轻七氟烷诱导的新生大鼠认知功能障碍［J］.陆军军医大学学报，2025，47（24）：3077-3088.DOI：10.16016/j.2097-0927.202509053. DOI：

CHEN Y，YANG M，YANG Y H，et al.Dexmedetomidine alleviates sevoflurane-induced cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway［J］.J Army Med Univ，2025，47（24）：3077-3088.DOI：10.16016/j.2097-0927.202509053. DOI：

摘要

目的

探讨右美托咪定（dexmedetomidine，Dex）是否通过调控哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）/核转录因子-κB（nuclear factor kappaB，NF-κB）信号通路，改善七氟烷（sevoflurane，Sev）诱导的新生大鼠认知障碍。

方法

将50只6日龄SD大鼠，体质量（9.5~11.5）g，按照随机数字表法分为（

=10）：假手术（Sham）组、模型（Model）组、Dex低剂量（Dex-L）组、Dex高剂量（Dex-H）组及mTOR/NF-κB信号通路激活剂佛波酯（phorbol12-myristate13-acetate，PMA）组；其中，Model、Dex-L、Dex-H、PMA组大鼠以在封闭箱内通入2%Sev+21%O

进行造模，Sham组给予新鲜空气；在放入箱内前2 h，Dex-L、Dex-H组大鼠分别腹腔注射10 μg/kg和30 μg/kg的Dex，PMA组大鼠腹腔注射30 μg/kg的Dex和5 mg/kg的PMA；Sham组和Model组大鼠腹腔注射等浓度的生理盐水。通过新物体识别实验和跳台试验评估认知功能、学习和记忆功能；激光散斑成像检测脑血流灌注；尼氏染色和透射电镜观察海马神经元及突触超微结构损伤；TUNEL试剂盒染色检测细胞凋亡；实时荧光定量聚合酶链

式反应（quantitative real-time polymerase chain reaction，qRT-PCR）检测大鼠脑组织海马区mTOR、NF-κB、突触后致密物蛋白（postsynaptic density protein，PSD）95和突触生长素（synaptophysin，SYP）、突触素（synapsin， SYN）、突触蛋白微管相关蛋白-2（microtubule associated protein-2，Map-2）、B淋巴细胞瘤-2（B cell lymphoma-2，Bcl-2）和Bcl-2相关X蛋白（Bcl2-associated x protein，Bax）的mRNA的表达；Western blot法检测大鼠海马组织中mTOR、磷酸化mTOR（phospho-mTOR，p-mTOR）、NF-κB、磷酸化NF-κB（phospho-NF-κB，p-NF-κB）、Bcl-2和Bax的表达。

结果

与Sham组相比，Model组大鼠辨别指数和跳台潜伏期显著降低，错误次数增加（

0.05），脑血流灌注减少，海马神经元数量减少，突触结构损伤，凋亡率升高，p-mTOR、p-NF-κB、Bax的mRNA和蛋白的表达上调，而SYN、Map-2、SYP、PSD95的mRNA的表达下调（

0.05），Bcl-2的mRNA和蛋白的表达下调（

0.05

）。

Dex干预后，上述指标均显著改善（

0.05），且高剂量效果更优。PMA可部分逆转Dex-H的保护作用，重新激活mTOR/NF-κB信号，加重神经元损伤（

0.05

）。

结论

Dex可能通过抑制mTOR/NF-κB信号通路，抑制Sev诱导的海马神经元凋亡，从而缓解新生大鼠的认知功能障碍。

Abstract

Objective

To explore whether dexmedetomidine (Dex) improves sevoflurane (Sev)-induced cognitive impairment in neonatal rats by regulating mammalian rapamycin target protein (mTOR)/nuclear factor-κB (NF-κB) signaling pathway.

Methods

Fifty neonatal SD rats (aged 6 d

weighing 9.5~11.5 g) were randomly divided into 5 groups: sham operation (Sham) group

model (Model) group

low-dose Dex (Dex-L) group

high-dose Dex (Dex-H) group

and phorbol 12-myristate 13-acetate (PMA) group (an activator of mTOR/NF-κB signaling pathway)

with 10 animals in each group. The rats in the Sham group were placed in a sealed chamber containing fresh air

while those rats from the other 4 groups were exposed to 2% Sev+21% O₂ for modeling. In 2 h before chamber placement

the Dex-L and Dex-H groups received an intraperitoneal injection of 10 and 30 μg/kg Dex

respectively

and the PMA group received an intraperitoneal injection of 30 μg/kg Dex and 5 mg/kg PMA. The rats in the Sham and Model groups were given an intraperitoneal injection of equivalent volume of normal saline. Cognitive function and learning and memory abilities were evaluated with novel object recognition test and step-down inhibitory avoidance test. Laser speckle contrast imaging (LSCI) was used to observe cerebral blood flow; Nissl staining and transmission electron microscopy were employed to observe the ultrastructure of hippocampal neurons and synapses. TUNEL staining was perform to detect the cell apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the expression levels of mTOR

NF-κB

postsynaptic density protein 95 (PSD95)

synaptophysin (SYP)

synapsin (SYP)

microtubule-associated protein-2 (Map-2)

B-cell lymphoma-2 (Bcl-2)

and Bcl-2-associated X protein (Bax) in the hippocampal tissue. Western blotting was conducted to detect the protein levels of mTOR

p-mTOR

NF-κB

p-NF-κB

Bcl-2

and Bax in the hippocampal tissue.

Results

Compared with the Sham group

the Model group exhibited significantly lower discrimination index and shorter platform jumping latency

increased number of errors (

0.05)

reduced cerebral blood perfusion

decreased number of hippocampal neurons

damaged synaptic structure

raised apoptotic rate

enhanced expression of p-mTOR

p-NF-κB and Bax at mRNA and protein levels (

0.05)

while down-regulated mRNA levels of SYN

Map-2

SYP and PSD95 (

0.05)

and reduced mRNA and protein expression of Bcl-2 (

0.05). After the intervention of Dex

all the above indexes were significantly improved (

0.05)

and the effects of high dose were better. PMA partially reversed the protective effects of Dex-H

reactivated the signal of mTOR/NF-κB

and aggravated the neuronal damage (

0.05).

Conclusion

Dex may alleviate cognitive dysfunction in neonatal rats by inhibiting the mTOR/NF-κB signaling pathway and suppressing Sev-induced hippocampal neuronal apoptosis.

关键词

Keywords

references

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