Effects of Paroxetine Combined with Sulpiride on Depression and Hippocampal Ferroptosis in Rats
-
摘要:
目的 旨在探讨帕罗西汀联合舒必利对慢性不可预知应激（chronic unpredictable mild stress，CUMS）大鼠抑郁样行为及海马神经元铁死亡的影响。 方法 将大鼠随机分为6组：对照组、模型组、帕罗西汀组、舒必利组、联合用药组和联合用药+铁死亡诱导剂（Erastin）组，每组12只。建立CUMS大鼠模型。采用行为学实验（蔗糖偏好实验、旷场实验和悬尾实验）评估抑郁样行为。苏木素-伊红（hematoxylin-eosin，HE）和尼氏染色检测大鼠海马组织神经元损伤。检测大鼠海马组织中氧化应激和Fe2+含量。Western blot检测溶质载体家族 7 成员 11（solute carrier family 7 member 11，SLC7A11）和谷胱甘肽过氧化物酶 4（glutathione peroxidase 4，GPX4）蛋白表达水平。 结果 与对照组相比，模型组大鼠的蔗糖偏好率、运动总距离、直立次数、水平穿越格数、谷胱甘肽过氧化物酶（glutathione peroxidase，GSH-PX）水平、SLC7A11、GPX4蛋白表达水平显著降低（P < 0.05），悬尾不动时间、活性氧（reactive oxygen species，ROS）、丙二醛（malondialdehyde，MDA）、Fe2+水平显著增加（P < 0.05）。与模型组相比，帕罗西汀组和舒必利组大鼠的蔗糖偏好率、运动总距离、直立次数、水平穿越格数、GSH-PX水平、SLC7A11、GPX4蛋白表达水平显著增加（P < 0.05），悬尾不动时间、ROS、MDA、Fe2+水平显著降低（P < 0.05）。与帕罗西汀组和舒必利组相比，联合用药组大鼠的蔗糖偏好率、运动总距离、直立次数、水平穿越格数、GSH-PX水平、SLC7A11、GPX4蛋白表达水平显著增加（P < 0.05），悬尾不动时间、ROS、MDA、Fe2+水平显著降低（P < 0.05）。与联合用药组相比，联合用药+Erastin组大鼠的蔗糖偏好率、运动总距离、直立次数、水平穿越格数、GSH-PX水平、SLC7A11、GPX4蛋白表达水平显著降低（P < 0.05），悬尾不动时间、ROS、MDA、Fe2+水平显著增加（P < 0.05）。 结论 帕罗西汀与舒必利联合应用的效果优于单一用药，可能通过抑制海马神经元铁死亡过程，从而显著改善CUMS大鼠的抑郁样行为表现。 Abstract:Objective To investigate the effects of paroxetine combined with sulpiride on depressive-like behaviors and ferroptosis of hippocampal neurons in rats with chronic unpredictable mild stress （CUMS）. Methods Rats were randomly divided into 6 groups: control group, model group, paroxetine group, sulpiride group, combined treatment group, and combined treatment + ferroptosis inducer （Erastin） group, with 12 rats in each group. The CUMS rat model was established. Depressive-like behaviors were evaluated using behavioral tests （sucrose preference test, open field test, and tail suspension test）. Hematoxylin-eosin （HE） and Nissl staining were performed to detect neuronal damage in rat hippocampal tissues. Oxidative stress and Fe2+ levels in rat hippocampal tissues were measured. Western blot was used to detect the protein expression levels of solute carrier family 7 member 11 （SLC7A11） and glutathione peroxidase 4 （GPX4）. Results Compared with the control group, the model group showed significantly reduced sucrose preference rate, total movement distance, rearing frequency, horizontal crossing grid numbers, glutathione peroxidase （GSH-PX） levels, and SLC7A11 and GPX4 protein expression levels（P < 0.05）, while tail suspension immobility time and reactive oxygen species （ROS）, malondialdehyde （MDA） and Fe2+ levels were significantly increased （P < 0.05）. Compared with the model group, the paroxetine group and sulpiride group exhibited significantly higher sucrose preference rate, total movement distance, rearing frequency, horizontal crossing grid numbers, GSH-PX level, SLC7A11 and GPX4 protein expression levels （P < 0.05）, while tail suspension immobility time and ROS, MDA, and Fe2+ levels were significantly decreased （P < 0.05）. Compared with the paroxetine group and sulpiride group, the combined treatment group showed significant increased sucrose preference rate, total movement distance, rearing frequency, horizontal crossing grid numbers, GSH-PX levels, SLC7A11 and GPX4 protein expression levels （P < 0.05）, whereas the tail suspension immobility time, ROS, MDA and Fe2+ levels were significantly decreased （P < 0.05）. Compared with the combined treatment group, the combined treatment + Erastin group showed significantly reduced sucrose preference rate, total movement distance, rearing frequency, horizontal crossing grid numbers, GSH-PX levels, and SLC7A11 and GPX4 protein expression levels （P < 0.05）, while tail suspension immobility time and ROS, MDA, and Fe2+ levels were significantly increased （P < 0.05）. Conclusions The combination of paroxetine and sulpiride is more effective than either drug alone, and may significantly improve depressive-like behaviors in CUMS rats by inhibiting the ferroptosis process of hippocampal neurons. -
Key words:
- Paroxetine /
- Sulpiride /
- Chronic unpredictable mild stress /
- Depression /
- Ferroptosis
-
图 1 帕罗西汀联合舒必利对大鼠行为学指标的影响
A：蔗糖偏好率；B～D：旷场实验的运动总距离、直立次数和水平穿越格数；E：悬尾不动时间；**P < 0.01。
Figure 1. Effects of paroxetine combined with sulpiride on behavioral parameters in rats
图 2 帕罗西汀联合舒必利对大鼠海马组织形态的影响
A：HE染色（×400）；B～C：尼氏染色（×400）；**P < 0.01。
Figure 2. Effect of paroxetine combined with sulpiride on the morphology of hippocampus in rats
图 3 帕罗西汀联合舒必利对大鼠海马组织氧化应激的影响
A.ROS；B.MDA；C.GSH-PX；**P < 0.01。
Figure 3. Effect of paroxetine combined with sulpiride on oxidative stress in rat hippocampual tissue
图 4 帕罗西汀联合舒必利对大鼠海马组织铁含量的影响
**P < 0.01。
Figure 4. Effect of paroxetine combined with sulpiride on Fe2+ levels in rat hippocampal tissue
图 5 帕罗西汀联合舒必利对大鼠线粒体损伤的影响（×10 000）
注：箭头指向损伤线粒体嵴断裂。
Figure 5. Effects of paroxetine combined with sulpiride on mitochondrial damage in rats （ × 10 000 ）
图 6 帕罗西汀联合舒必利对大鼠铁死亡通路SLC7A11/GPX4通路的影响
A～C：蛋白印迹检测各组大鼠海马组织SLC7A11和GPX4蛋白表达水平；**P < 0.01。
Figure 6. Effects of paroxetine combined with sulpiride on ferroptosis pathway SLC7A11/GPX4 pathway in rats
图 7 帕罗西汀联合舒必利通过抑制铁死亡对各组大鼠行为学指标的影响
A：蔗糖偏好率；B～D：旷场实验的运动总距离、直立次数和水平穿越格数；E：悬尾不动时间；**P < 0.01。
Figure 7. Effect of paroxetine combined with sulpiride on behavioral indexes of rats in each group by inhibiting ferroptosis
图 8 帕罗西汀联合舒必利对大鼠海马组织形态的影响
A：HE染色（×400）；B～C：尼氏染色（×400）；**P < 0.01。
Figure 8. Effects of paroxetine combined with sulpiride on the morphology of hippocampus in rats
图 9 帕罗西汀联合舒必利通过抑制铁死亡对各组大鼠海马组织氧化应激和铁含量的影响
A：ROS；B：MDA；C：GSH-PX；D：Fe2+；**P < 0.01。
Figure 9. Effects of paroxetine combined with sulpiride on oxidative stress and Fe2+ levels in hippocampus of rats in each group by inhibiting ferroptosis
图 10 电镜观察线粒体超微结构（×10 000）
A：联合用药组；B：联合用药+Erastin组。注：箭头指向损伤线粒体嵴断裂
Figure 10. Electron microscopic observation of mitochondrial ultrastructure （ × 10 000 ）
-
[1] Goodwin G M, Stein D J. Generalised anxiety disorder and depression: Contemporary treatment approaches[J]. Adv Ther, 2021, 38(Suppl 2): 45-51. [2] Shorey S, Ng E D, Wong C H J. Global prevalence of depression and elevated depressive symptoms among adolescents: A systematic review and meta-analysis[J]. British J Clinic Psychol, 2022, 61(2): 287-305. doi: 10.1111/bjc.12333 [3] Li X, Tian Y, Phillips M R, et al. Protocol of a prospective community-based study about the onset and course of depression in a nationally representative cohort of adults in China: The China Depression Cohort Study-I[J]. BMC Public Health, 2023, 23(1): 1617. doi: 10.1186/s12889-023-16542-6 [4] Chen P, Bai W, Li X H, et al. Research on major depression in China: A perspective from bibliometric analysis[J]. J Affect Disord, 2022, 315: 174-181. doi: 10.1016/j.jad.2022.07.046 [5] Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis[J]. J Psychiatr Res, 2022, 151: 693-709. doi: 10.1016/j.jpsychires.2022.04.037 [6] Li C, Ge H, Huang J, et al. Resveratrol alleviates depression-like behaviors by inhibiting ferroptosis via AKT/NRF2 pathway[J]. Brain Res Bull, 2025, 220: 111136. doi: 10.1016/j.brainresbull.2024.111136 [7] Ma X, Shi W, Wang Z, et al. Butyric acid and valeric acid attenuate stress-induced ferroptosis and depressive-like behaviors by suppressing hippocampal neuroinflammation[J]. J Transl Med, 2025, 23(1): 974. doi: 10.1186/s12967-025-06950-0 [8] Zeng M, Gong A, Wu Z. Paroxetine combined with traditional Chinese medicine prescriptions in the treatment of postpartum depression: A systematic review of randomized controlled trials[J]. Front Neuroendocrinol, 2022, 67: 101019. doi: 10.1016/j.yfrne.2022.101019 [9] Dilinuer Abulikemu, Wang Y, Zeng F C, et al. Study on the mechanisms of acupuncture combined with paroxetine in the treatment of mild to moderate depression based on DNA methylation analysis[J]. Acupuncture Research, 2024, 49(7): 751-759. [10] Mohyeldin S M, Samy W M, Ragab D, et al. Precisely fabricated sulpiride-loaded nanolipospheres with ameliorated oral bioavailability and antidepressant activity[J]. Int J Nanomedicine, 2021, 16: 2013-2044. doi: 10.2147/IJN.S296726 [11] Zhao D, Liu C. Effects of paroxetine combined with sulpiride on sleep status and quality of life in patients with depressive episodes[J]. Front Psychiatry, 2025, 16: 1600675. doi: 10.3389/fpsyt.2025.1600675 [12] 钱婷婷, 邹玲, 高志, 等. 基于SLC7A11/GPX4信号通路探讨 “通督调神” 针刺对抑郁症模型大鼠海马神经元铁死亡的影响[J]. 中国针灸, 2025, 45(8): 1120-1127. doi: 10.13703/j.0255-2930.20240917-k0001 [13] 程闯, 李娟, 王红雷, 等. 帕罗西汀通过Akt/GSK3β/CREB通路对焦虑大鼠行为学的改善作用[J]. 河北医药, 2023, 45(5): 699-703. doi: 10.3969/j.issn.1002-7386.2023.05.013 [14] 徐文倩, 肖玲, 谢银平, 等. Erastin对大鼠焦虑抑郁样行为及海马铁死亡相关蛋白表达的影响[J]. 中华行为医学与脑科学杂志, 2023, 32(8): 673-679. doi: 10.3760/cma.j.cn371468-20221124-00712 [15] 袁木发, 费素娟. 氟哌噻吨美利曲辛片联合舒必利治疗功能性消化不良伴有焦虑、抑郁患者的临床疗效[J]. 江苏医药, 2021, 47(1): 58-61+65. doi: 10.19460/j.cnki.0253-3685.2021.01.015 [16] 王叶欣, 庞芳, 唐成林. 针药结合对抑郁症大鼠脑-肠轴功能的影响[J]. 重庆医科大学学报, 2022, 47(12): 1465-1471. doi: 10.13406/j.cnki.cyxb.003153 [17] 贯东艳, 张米佳, 侯志颍, 等. 胡椒提取物改善慢性束缚应激小鼠抑郁样行为的潜在机制研究[J]. 中国比较医学杂志, 2025, 35(2): 58-71+84. doi: 10.3969/j.issn.1671-7856.2025.02.006 [18] Bai W, Zhang J, Smith R D, et al. Inter-relationship between cognitive performance and depressive symptoms and their association with quality of life in older adults: A network analysis based on the 2017-2018 wave of Chinese Longitudinal Healthy Longevity Survey (CLHLS)[J]. J Affect Disord, 2023, 320: 621-627. doi: 10.1016/j.jad.2022.09.159 [19] Zhang C, Chen L, Duan Y Y, et al. Drug-drug interaction of paroxetine on olanzapine and initial dosage optimization in patients with major depressive disorder based on population pharmacokinetics[J]. Front Psychiatry, 2025, 16: 1538996. doi: 10.3389/fpsyt.2025.1538996 [20] Guan L N, Li L, Li H H, et al. Research progress in the treatment of postpartum depression[J]. Cell Mol Neurobiol, 2025, 45(1): 35. doi: 10.1007/s10571-025-01542-4 [21] Silva S, Bicker J, Fialho S, et al. Intranasal delivery of paroxetine: A preclinical study on pharmacokinetics, depressive-like behaviour, and neurochemical sex differences[J]. Biochem Pharmacol, 2024, 223: 116184. doi: 10.1016/j.bcp.2024.116184 [22] 沈富伟, 周弋人, 缪礁丹. 帕罗西汀与阿米替林联用对卒中后抑郁大鼠额前皮质区与海马区的单胺类递质、脑源性神经营养因子水平的改变[J]. 脑与神经疾病杂志, 2021, 29(3): 160-165. [23] 武小玲, 王森岩, 赵思俊, 等. 选择性5-羟色胺再摄取抑制剂联合用药治疗难治性抑郁症研究进展[J]. 中国药理学与毒理学杂志, 2022, 36(10): 776-783. doi: 10.3867/j.issn.1000-3002.2022.10.007 [24] Liang Y, Yang Y, Huang R, et al. Conjugation of sulpiride with a cell penetrating peptide to augment the antidepressant efficacy and reduce serum prolactin levels[J]. Biomed Pharmacother, 2024, 174: 116610. doi: 10.1016/j.biopha.2024.116610 [25] Péczely L, Dusa D, Lénárd L, et al. The antipsychotic agent sulpiride microinjected into the ventral pallidum restores positive symptom-like habituation disturbance in MAM-E17 schizophrenia model rats[J]. Sci Rep, 2024, 14(1): 12305. doi: 10.1038/s41598-024-63059-y [26] 刘威. 低剂量舒必利治疗抑郁症的临床疗效及对预后的影响[J]. 当代医学, 2021, 27(17): 129-130. doi: 10.3969/j.issn.1009-4393.2021.17.053 [27] 杨柳, 周云云. 帕罗西汀联合小剂量舒必利治疗社交恐惧合并抑郁的疗效[J]. 中国健康心理学杂志, 2018, 26(6): 807-810. doi: 10.13342/j.cnki.cjhp.2018.06.003 [28] 武长继, 杨柳, 张新宇. 帕罗西汀、舒必利联合治疗年轻女性社交恐惧效果及对神经递质、睡眠结构的影响[J]. 昆明医科大学学报, 2023, 44(12): 159-164. doi: 10.12259/j.issn.2095-610X.S20231225 [29] Markov D D, Novosadova E V. Chronic unpredictable mild stress model of depression: Possible sources of poor reproducibility and latent variables[J]. Biology, 2022, 11(11): 1621. doi: 10.3390/biology11111621 [30] Shen J, Hao C, Yuan S, et al. Acupuncture alleviates CUMS-induced depression-like behaviors of rats by regulating oxidative stress, neuroinflammation and ferroptosis[J]. Brain Res, 2024, 1826: 148715. doi: 10.1016/j.brainres.2023.148715 [31] Wu H, Luan Y, Wang H, et al. Selenium inhibits ferroptosis and ameliorates autistic-like behaviors of BTBR mice by regulating the Nrf2/GPx4 pathway[J]. Brain Res Bull, 2022, 183: 38-48. doi: 10.1016/j.brainresbull.2022.02.018 [32] Sowa-Kućma M, Styczeń K, Siwek M, et al. Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts[J]. Prog Neuro Psychopharmacol Biol Psychiatry, 2018, 81: 372-383. doi: 10.1016/j.pnpbp.2017.08.024 [33] Li E, Yin H, Su M, et al. Inhibition of ferroptosis alleviates chronic unpredictable mild stress-induced depression in mice via tsRNA-3029b[J]. Brain Res Bull, 2023, 204: 110773. doi: 10.1016/j.brainresbull.2023.110773 [34] Wang L, Xu R, Huang C, et al. Targeting the ferroptosis crosstalk: Novel alternative strategies for the treatment of major depressive disorder[J]. Gen Psychiatr, 2023, 36(5): e101072. doi: 10.1136/gpsych-2023-101072 [35] Dang R, Wang M, Li X, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway[J]. J Neuroinflammation, 2022, 19(1): 41. doi: 10.1186/s12974-022-02400-6 [36] Jiang X, Stockwell B R, Conrad M. Ferroptosis: Mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. doi: 10.1038/s41580-020-00324-8 -
下载:
点击查看大图
计量
- 文章访问数: 2
- HTML全文浏览量: 3
- PDF下载量: 0
- 被引次数: 0
