Exploration of the mechanism of cognitive impairment induced by ketamine in mice based on metabolomics

LUO Tingting; YAO Xiaoxiao; ZHAN Xinyi; MA Yiru; GAO Ting; WEI Ying

doi:10.6039/j.issn.1001-0408.2025.12.04

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Exploration of the mechanism of cognitive impairment induced by ketamine in mice based on metabolomics

更新时间：2025-09-23

- Exploration of the mechanism of cognitive impairment induced by ketamine in mice based on metabolomics
- ZHONGGUO YAOFANG Vol. 36, Issue 12, Pages: 1436-1441(2025)
- 作者机构：
  
  川北医学院药学院，四川南充　637000
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2025.12.04
  CLC： R965
- Received：22 January 2025，
  
  Revised：2025-05-15，
  
  Accepted：21 May 2025，
  
  Published：30 June 2025
- 稿件说明：
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罗婷婷,姚潇潇,詹欣艺,等.基于代谢组学探讨氯胺酮致小鼠认知障碍的机制 [J].中国药房,2025,36(12):1436-1441.

LUO Tingting,YAO Xiaoxiao,ZHAN Xinyi,et al.Exploration of the mechanism of cognitive impairment induced by ketamine in mice based on metabolomics[J].ZHONGGUO YAOFANG,2025,36(12):1436-1441.
罗婷婷,姚潇潇,詹欣艺,等.基于代谢组学探讨氯胺酮致小鼠认知障碍的机制 [J].中国药房,2025,36(12):1436-1441. DOI： 10.6039/j.issn.1001-0408.2025.12.04.

LUO Tingting,YAO Xiaoxiao,ZHAN Xinyi,et al.Exploration of the mechanism of cognitive impairment induced by ketamine in mice based on metabolomics[J].ZHONGGUO YAOFANG,2025,36(12):1436-1441. DOI： 10.6039/j.issn.1001-0408.2025.12.04.

摘要

目的

基于代谢组学探讨氯胺酮致小鼠认知障碍的潜在机制。

方法

将雄性C57BL/6小鼠随机分为对照组和氯胺酮组（25 mg/kg），每组12只。各组小鼠腹腔注射生理盐水或相应药液，每天4次，连续10 d。分别在最后2 d通过Y迷宫实验和新物体识别实验进行小鼠行为学测试，观察其前额叶皮质（PFC）组织病理学形态变化；采用超高效液相色谱-串联质谱技术分析PFC组织的代谢物变化，筛选差异代谢物并进行通路富集分析。

结果

与对照组比较，氯胺酮组小鼠PFC组织神经元形态不一，细胞核周围出现空腔，核深染细胞增多，尼氏染色阳性区域的平均光密度值显著降低，其交替率和辨别指数亦显著降低（

＜0.05或

＜0.01）。两组小鼠的PFC组织样品中，共有114种差异代谢物，其中表达上调73种、表达下调41种，包括谷氨酰胺、琥珀酸、酮戊二酸及胆碱等；上述差异代谢物主要富集于丙氨酸、天冬氨酸和谷氨酸代谢，精氨酸和脯氨酸代谢，γ氨基丁酸能突触，嘧啶代谢，胆碱能突触等通路。

结论

氯胺酮能诱导小鼠认知障碍，其神经毒性与突触传导、能量代谢异常及神经免疫调节紊乱有关。

Abstract

OBJECTIVE

To explore the potential mechanism of ketamine-induced cognitive impairment in mice based on metabolomics.

METHODS

Male C57BL/6 mice were randomly divided into control group and ketamine group （25 mg/kg）， with 12 mice in each group. Each group of mice was intraperitoneally injected with normal saline or corresponding drugs， 4 times a day， for 10 consecutive days. On the last 2 days of drug administration， the cognitive behavior was evaluated by Y maze and novel object recognition test， and the histopathological changes in the prefrontal cortex （PFC） were observed. Ultra-high performance liquid chromatography-tandem mass spectrometry technology was used to analyze the changes of metabolites in PFC， screen for differential metabolites， and perform pathway enrichment analysis.

RESULTS

Compared with the control group， the morphology of PFC neurons in the ketamine group of mice was inconsistent. There were cavities around the nucleus， and the number of deeply stained cells increased. The mean optical density value of the Nissl staining positive area was significantly reduced， and the alternation rate and discrimination index were significantly reduced （

＜0.05 or

＜0.01）. In the PFC tissue samples of mice of the two groups， there were a total of 114 differential metabolites， including 73 up-regulated and 41 down-regulated metabolites， including glutamine， succinic acid， ketoglutarate， and choline， etc. The differential metabolites mentioned above were mainly enriched in metabolism of alanine， aspartate and glutamate， metabolism of arginine and proline， γ aminobutyric acid synapses， pyrimidine metabolism， cholinergic synapses pathways， etc.

CONCLUSIONS

Ketamine can induce cognitive impairment in mice. Its neurotoxicity is related to abnormal synaptic transmission and energy metabolism， and neuroimmune regulation disorders.

关键词

Keywords

references

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