Page 26 - 《中国药房》2025年12期

基于代谢组学探讨氯胺酮致小鼠认知障碍的机制
Δ

＊
罗婷婷 ，姚潇潇，詹欣艺，马忆茹，高 婷，魏 莹（川北医学院药学院，四川 南充 637000）
#
中图分类号 R965 文献标志码 A 文章编号 1001-0408（2025）12-1436-06
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（P＜0.05 或 P＜
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。
关键词 氯胺酮；认知障碍；神经毒性；代谢组学；代谢通路

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（School of Pharmacy， North
Sichuan Medical College， Sichuan Nanchong 637000， China）

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 （P＜0.05 or P＜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.
KEYWORDS ketamine； cognitive impairment； neurotoxicity； metabolomics； metabolic pathways

氯胺酮是苯环己哌啶衍生物，是 N-甲基-D-天冬氨 酸（N-methyl-D-aspartate，NMDA）受体非竞争性拮抗剂，
[1]
被广泛应用于临床麻醉和镇痛 。近期研究指出，低剂
Δ 基金项目 国家自然科学基金项目（No.82404779）；四川省大学 [2―3]
量氯胺酮具有快速抗抑郁潜力和神经保护作用 ，对
生创新训练计划项目（No.S202410634094）；川北医学院博士科研启动
[4]
创伤后应激障碍也有明显的改善效果 。然而，尽管氯
基金项目（No.CBY23-QDA03）
＊第一作者 助理实验师，硕士。研究方向：药物分析及药物质量 胺酮具有重要的医疗价值，但潜在的滥用风险极大地限
控制。E-mail：417318589@qq.com
制了该药在临床上的应用。氯胺酮具有强致幻性，长期
# 通信作者 副教授，博士。研究方向：毒物分析及毒性机制。E-
mail：weiyingnc@nsmc.edu.cn 滥用可引发多种精神障碍疾病的典型症状，包括焦虑、

· 1436 · China Pharmacy 2025 Vol. 36 No. 12 中国药房 2025年第36卷第12期