氟西汀通过调控海马小胶质细胞极化改善小鼠术后认知功能障碍

Fluoxetine ameliorates postoperative cognitive dysfunction in mice by regulatinghippocampal microglial polarization

摘要

目的 探讨氟西汀对术后认知功能障碍小鼠海马小胶质细胞极化作用及认知功能的影响。方法 将18月龄雄性小鼠分为假手术组、POCD模型组和氟西汀治疗组,利用行为学实验检测小鼠情绪认知相关行为;免疫荧光标记检测海马区Iba1、CD86和CD206阳性细胞表达情况;RT-qPCR检测IL-1β、TNF-α的表达水平,免疫蛋白印迹检测小鼠海马组织小胶质细胞极化相关蛋白的表达水平。结果 水迷宫实验结果发现氟西汀改善了小鼠认知行为;免疫荧光检测结果发现CD86在POCD组表达明显增强,氟西汀治疗组表达下降,CD206表达在治疗组增强,模型组表达较弱,RT-qPCR检测发现POCD组IL-1β、TNF-α mRNA表达增高,治疗组降低,免疫蛋白印迹检测发现治疗组CD86降低,CD206表达升高。结论 氟西汀促进了小胶质细胞M1向M2的极化,改善了小鼠认知水平。

Abstract

Objective To investigate the effects of fluoxetine on the polarization of hippocampal microglia and cognitive function in mice with postoperative cognitive dysfunction (POCD). Methods Eighteen-month-old male mice were divided into three groups: sham operation group, POCD group, and fluoxetine treatment group. Behavioral experiments were used to detect cognitive and emotional behaviors in the mice. Immunofluorescence labeling was used to detect the expression of Iba1, CD86, and CD206 positive cells in the hippocampal region. RT-qPCR was used to detect the expression levels of IL-1β and TNF-α. Western blotting was used to detect the expression levels of microglial polarization-related proteins in the hippocampal tissue of mice. Results The results of the water maze experiment showed that fluoxetine improved the cognitive behavior of the mice. Immunofluorescence results showed that the expression of CD86 was significantly enhanced in the POCD group, while it decreased in the treatment group. The expression of CD206 was enhanced in the treatment group but weak in the model group. RT-qPCR detection revealed that the mRNA expression of IL-1βand TNF-α was increased in the POCD group and reduced in the treatment group. Western blotting detected decreased CD86 and increased CD206 expression in the treatment group. Conclusion Fluoxetine promotes the polarization of microglia from the M1 to M2 phenotype, thereby improving the cognitive level of the mice.

关键词

小鼠 / 海马 / 小胶质细胞 / 细胞极化

Key words

mouse / hippocampus / microglia / cell polarization

[1] Olotu C. Postoperative neurocognitive disorders[J]. Curr Opin Anaesthesiol, 2020, 33(1):101-108.
[2] Li Y, Peng Q, Lu J, et al. Cognitive change associated with anesthesia and surgery: An introduction to POCD for neuroscientists[J]. J Integr Neurosci, 2025, 24(7): 36785.
[3] Vidal-itriago A, Radford R A W, Aramideh J A, et al. Microglia morphophysiological diversity and its implications for the CNS,l[J]. Front Immuno, 2022, 19(13): 997786.
[4] Li J, Shi C, Ding Z, et al. Glycogen synthase kinase 3β promotes postoperative cognitive dysfunction by inducing the m1 polarization and migration of microglia[J]. Mediators Inflamm, 2020, 28(7): 7860829.
[5] Wang Y, Cai Z, Zhan G, et al. Caffeic acid phenethyl ester suppresses oxidative stress and regulates M1/M2 microglia polarization via sirt6/Nrf2 pathway to mitigate cognitive impairment in aged mice following anesthesia and surgery[J]. Antioxidants (Basel), 2023, 12(3): 714-720.
[6] Zhao L, Huang Q, Li N, et al. HMGB1 promotes LPS-induced M1 polarization and apoptosis in microglia by mediating the expression of immune and inflammation-related genes[J]. Brain Res Bull, 2025(233): 111615.
[7] Li C, Cong Y, Song W, et al. Irisin regulates microglia M1/M2 polarization and promotes autophagy through the sirt3 pathway to alleviate POCD[J]. J Neuroimmune Pharmacol, 2025, 20(1): 34.
[8] Reddihough D S, Marraffa C, Mouti A, et al. Effect of fluoxetine on obsessive-compulsive behaviors in children and adolescents with autism spectrum disorders: A randomized clinical trial[J]. Jama, 2019, 322(16): 1561-1569.
[9] Caiaffo V, Oliveira B D, De Sá F B, et al. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine[J]. Pharmacol Res Perspect, 2016, 4(3): e00231.
[10] Lanquillon S, Krieg J C, Bening-abu-shach U, et al. Cytokine production and treatment response in major depressive disorder[J]. Neuropsychopharmacology, 2021, 22(4): 370-379.
[11] Lou C, Fang M, Ye S, et al. Fluoxetine protects against inflammation and promotes autophagy in mice model of post-traumatic stress disorder[J]. Behav Brain Res, 2022(433): 114004.
[12] Liu Q, Sun Y M, Huang H, et al. Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation[J]. J Neuroinflammation, 2021, 18(1): 41.
[13] Kang X, Xie Z, Yang Y, et al. Hippocampal GPR35 is involved in the depression-like behaviors induced by inflammation and mediates the antidepressant effects of fluoxetine in mice[J]. Brain Behav Immun, 2025, 126: 189-213.
[14] Fang Y, Ding X, Zhang Y, et al. Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT(2B)R/β-arrestin2 pathway[J]. J Neuroinflammation, 2022, 19(1): 23.
[15] Gao C, Jiang J, Tan Y, et al. Microglia in neurodegenerative diseases: Mechanism and potential therapeutic targets[J]. Signal Transduct Target Ther, 2023, 8(1): 359.
[16] Han X, Cheng X, Xu J, et al. Activation of TREM2 attenuates neuroinflammation via PI3K/Akt signaling pathway to improve postoperative cognitive dysfunction in mice[J]. Neuropharmacology, 2022(219): 109231.
[17] Du J, Chen C, Chen J. Cirsilineol improves anesthesia/surgery-induced postoperative cognitive dysfunction through attenuating oxidative stress and modulating microglia M1/M2 polarization[J]. PeerJ, 2024(12): e18507.
[18] Zhu Y, Wang Y, Yao R, et al. Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period[J]. J Neuroinflammation, 2017, 14(1): 6.
[19] 李光耀, 魏顺民, 井紫薇, 等. 川穹嗪通过减弱血脑屏障损伤改善老年小鼠术后神经认知障碍[J]. 空军军医大学学报, 2023, 44(4): 301-304.
Li Guangyao, Wei Shunmin, Jing Ziwei,et al. Tetramethylpyrazine improves postoperative neurocognitive disorders in old mice by attenuating blood-brain barrier injury[J]. J Air Force Med Univ, 2023, 44(4):301-403
[20] Soltesz I, Losonczy A. CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus[J]. Nat Neurosci, 2018, 21(4): 484-493.
[21] Espadas I, Ortiz O, García-sanz P, et al. Dopamine D2R is required for hippocampal-dependent memory and plasticity at the CA3-CA1 synapse[J]. Cereb Cortex, 2021, 31(4): 2187-2204.
[22] Fukushima S, Kurganov E, Hiratsuka D, et al. Effect of fluoxetine on proliferation and/or survival of microglia and oligodendrocyte progenitor cells in the fornix and corpus callosum of the mouse brain[J]. Pharmacol Rep, 2020, 72(2): 340-349.
[23] Du R H, Tan J, Sun X Y, et al. Fluoxetine inhibits NLRP3 inflammasome activation: Implication in depression[J]. Int J Neuropsychopharmacol, 2016, 19(9): 101093.
[24] Fuller R W, Wong D T, Robertson D W. Fluoxetine, a selective inhibitor of serotoninuptake[J]. Med Res Rev, 1991, 11(1): 17-34.
[25] Wan M, Ma Z, Han J, et al. 5-HT induces regulatory B cells in fighting against inflammation-driven ulcerative colitis[J]. Int Immunopharmacol, 2023, 125(Pt A): 111042.
[26] Fu X, Yan S, Hu Z, et al. Guhan Yangsheng Jing mitigates hippocampal neuronal pyroptotic injury and manifies learning and memory capabilities in sleep deprived mice via the NLRP3/Caspase1/GSDMD signaling pathway[J]. J Ethnopharmacol, 2024(326): 117972.
[27] Wang J, Zhang H. Serotonin mitigates depression in a rotenone-induced mouse Parkinson's disease model by inhibiting hippocampal neuronal pyroptosis and neuroinflammation[J]. Behav Brain Res, 2025(490): 115620.

基金资助

国家自然科学基金项目(82360242);新疆维吾尔自治区“天山英才”医药卫生领军人才计划项目(TSYC202401A091)