越鞠丸干预CUMS小鼠对抑郁样行为、功能性消化不良及PACAP/PAC1-R表达的影响

王艳; 高田田; 王子颖; 陈刚; 陶伟伟

doi:10.14148/j.issn.1672-0482.2024.0261

越鞠丸干预CUMS小鼠对抑郁样行为、功能性消化不良及PACAP/PAC1-R表达的影响

doi: 10.14148/j.issn.1672-0482.2024.0261

王艳^1,,
高田田¹,
王子颖²,
陈刚²,
陶伟伟^1, ,

1.
南京中医药大学中西医结合学院, 江苏南京 210023
2.
暨南大学中医学院, 广东广州 510632

基金项目:

国家自然科学基金面上项目 82274241

详细信息

作者简介:
王艳, 女, 博士研究生, E-mail: 20180931105@bucm.edu.cn

通讯作者:
陶伟伟, 男, 教授, 主要从事中医药防治抑郁症研究, E-mail: tw845@163.com

中图分类号: R285.5
计量
- 文章访问数: 75
- HTML全文浏览量: 27
- PDF下载量: 10
- 被引次数: 0
出版历程
- 收稿日期: 2023-11-09
- 网络出版日期: 2024-03-15
- 发布日期: 2024-03-10

Effects of Yueju Pill on Depressive Behavior, Functional Dyspepsia and PACAP/PAC1-R Expression in CUMS Mice

1.
School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
2.
School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China

摘要

摘要: 目的探讨越鞠丸对抑郁共病功能性消化不良小鼠抑郁样行为和胃肠功能的影响。方法将C57BL/6J小鼠随机分为对照组、模型组、越鞠丸低剂量组、越鞠丸高剂量组和阳性药组, 采用慢性不可预知温和应激(CUMS)构建共病模型, 通过行为学检测、尼氏染色评估小鼠抑郁样行为和神经元损伤; 胃肠组织病理、胃排空率、小肠推进率评估胃肠功能; ELISA法检测PACAP、VIP、IL-6、TNF-α、BDNF表达; Western blot检测PAC1-R、Vipr1、Vipr2蛋白表达。结果模型组小鼠表现出抑郁样行为, 海马尼氏体数量减少, 胃肠运动减慢, 血清炎症因子IL-6、TNF-α水平升高(P＜0.05, P＜0.01), PACAP、VIP、BDNF表达降低(P＜0.05, P＜0.01), 海马、胃窦、十二指肠组织PAC1-R、Vipr1、Vipr2表达降低(P＜0.05, P＜0.01)。与模型组比较, 越鞠丸低、高剂量组可改善除Vipr1、Vipr2之外的其他上述指标(P＜0.05, P＜0.01)。结论越鞠丸可通过PACAP/PAC1-R降低炎症因子, 升高BDNF水平, 改善CUMS小鼠抑郁样行为和功能性消化不良。
- 越鞠丸 /
- PACAP /
- PAC1-R /
- 抑郁 /
- 功能性消化不良
Abstract: OBJECTIVE To explore the effects of Yueju Pill on depression and gastrointestinal function in depressed co-morbid functional dyspepsia mice. METHODS C57BL/6J mice were randomly divided into control group, model group, Yueju Pill low-dose group, Yueju Pill high-dose group and positive drug group. A co-morbidity model was constructed using chronic unpredictable mild stress (CUMS), and the mice were assessed for depression-like behaviour and neuronal damage by behavioural tests and Nissl staining; gastrointestinal function was assessed by HE staining of gastric and intestinal tissues, gastric emptying rate, and small intestinal propulsive rate; PACAP, VIP, IL-6, TNF-α, and BDNF expression were detected by ELISA; PAC1-R, Vipr1, and Vipr2 protein expression were detected by protein immunoblotting. RESULTS Mice in the model group showed depression-like behaviour, reduced number of hippocampal nidus, slowed gastrointestinal motility, elevated serum inflammatory factors IL-6 and TNF-α (P < 0.05, P < 0.01), and reduced expression of PACAP, VIP, and BDNF (P < 0.05, P < 0.01), The PAC1-R, VPAC1-R, VPAC2-R expression decreased in the hippocampus and gastric sinus, duodenal tissue (P < 0.05, P < 0.01). Compared with the model group, the low and high dose groups of Yueju Pill improved the above indexes except for Vipr1 and Vipr2 (P < 0.05, P < 0.01). CONCLUSION Yueju Pill can reduce inflammatory factors through PACAP/PAC1-R, increase the level of BDNF, and improve the depression-like behaviour and gastrointestinal dysfunction in CUMS mice.
- Yueju Pill /
- PACAP /
- PAC1-R /
- depression /
- functional dyspepsia

HTML全文

图 1 越鞠丸对小鼠抑郁样行为的影响

注: 与对照组比较, ^##P＜0.01;与模型组比较, ^*P＜0.05, ^**P＜0.01。x±s, n=12。

Figure 1. Effects of Yueju Pill on depressive-like behavior in mice

下载: 全尺寸图片幻灯片

图 2 越鞠丸对小鼠胃窦组织、十二指肠组织形态的影响

Figure 2. Effects of Yueju Pill on gastric antrum tissue and duodenal tissue morphology in mice

下载: 全尺寸图片幻灯片

图 3 越鞠丸对小鼠胃排空率及小肠推进率的影响

注: A.胃排空率；B.小肠推进率。与对照组比较, ^##P＜0.01;与模型组比较, ^*P＜0.05, ^**P＜0.01。x±s, n=3。

Figure 3. Effects of Yueju Pill on gastric emptying rate and small intestinal propulsion rate in mice

下载: 全尺寸图片幻灯片

图 4 尼氏染色结果

Figure 4. Nissl staining results

下载: 全尺寸图片幻灯片

图 5 越鞠丸对小鼠海马、胃窦、十二指肠组织中PACAP、VIP含量的影响

注: 与对照组比较, ^##P＜0.01;与模型组比较, ^*P＜0.05, ^**P＜0.01。x±s, n=6。

Figure 5. Effects of Yueju Pill on PACAP and VIP contents in the hippocampus, gastric antrum, and duodenum tissues of mice

下载: 全尺寸图片幻灯片

图 6 越鞠丸对IL-6、TNF-α、BDNF表达的影响

注：A.血清IL-6；B.血清TNF-α；C.血清BDNF；D.海马组织BDNF。与对照组比较，^##P＜0.01；与模型组比较，^*P＜0.05，^**P＜0.01。x±s，n=6。

Figure 6. Effects of Yueju Pill on the expression of serum IL-6, TNF-α and BDNF in mice

下载: 全尺寸图片幻灯片

图 7 越鞠丸对Vipr1、Vipr2、PAC1-R蛋白表达的影响

注: A.海马组织; B.胃窦组织; C.十二指肠组织。与对照组比较, ^##P＜0.01;与模型组比较, ^*P＜0.05, ^**P＜0.01。x±s, n=6。

Figure 7. Effect of Yueju Pill on the expression of Vipr1, Vipr2 and PAC1-R proteins

下载: 全尺寸图片幻灯片

参考文献(22)

[1]	HUANG J, CAI Y Y, SU Y S, et al. Gastrointestinal symptoms during depressive episodes in 3256 patients with major depressive disorders: Findings from the NSSD[J]. J Affect Disord, 2021, 286: 27-32. doi: 10.1016/j.jad.2021.02.039
[2]	KOP W J. Somatic depressive symptoms, vital exhaustion, and fatigue: Divergent validity of overlapping constructs[J]. Psychosom Med, 2012, 74(5): 442-445. doi: 10.1097/PSY.0b013e31825f30c7
[3]	张煜萱, 崔博, 邹之璐, 等. 越鞠丸治疗气郁体质抑郁症患者及改善血清BDNF水平的临床对照研究[J]. 辽宁中医杂志, 2018, 45(5): 960-963. https://www.cnki.com.cn/Article/CJFDTOTAL-LNZY201805021.htm ZHANG Y X, CUI B, ZOU Z L, et al. Clinical observation on effect of Yueju pill in treating qi-stagnation constitution depression patients[J]. Liaoning J Tradit Chin Med, 2018, 45(5): 960-963. https://www.cnki.com.cn/Article/CJFDTOTAL-LNZY201805021.htm
[4]	李劲亮. 越鞠丸辅治肝胃不和型功能性消化不良的临床效果观察[J]. 临床合理用药杂志, 2018, 11(23): 40-41. https://www.cnki.com.cn/Article/CJFDTOTAL-PLHY201823022.htm LI J L. Clinical observation of Yueju Pill in adjuvant treatment of functional dyspepsia with disharmony between liver and stomach[J]. Chin J Clin Ration Drug Use, 2018, 11(23): 40-41. https://www.cnki.com.cn/Article/CJFDTOTAL-PLHY201823022.htm
[5]	REN L, ZHANG H L, TAO W W, et al. Hippocampal pituitary adenylate cyclase-activating polypeptide mediates rapid antidepressant-like effects of Yueju pill[J]. Neuropeptides, 2023, 101: 102350. doi: 10.1016/j.npep.2023.102350
[6]	杜鹃, 柯道平, 孔德虎. 垂体腺苷酸环化酶激活肽对胃肠道分泌与运动的影响[J]. 四川生理科学杂志, 2003(1): 1-4. doi: 10.3969/j.issn.1671-3885.2003.01.001 DU J, KE D P, KONG D H. Effects of pituitary adenylate cyclase activating peptide on gastrointestinal secretion and motility[J]. Sichuan J Physiol Sci, 2003(1): 1-4. doi: 10.3969/j.issn.1671-3885.2003.01.001
[7]	郑劼, 许一凡, 陈艳燕, 等. 甘麦大枣汤联合氟西汀通过调控肠道菌群改善慢性应激小鼠抑郁症状的研究[J]. 南京中医药大学学报, 2020, 36(5): 667-674. http://xb.njucm.edu.cn/article/id/zr20200515 ZHENG J, XU Y F, CHEN Y Y, et al. Ganmai Dazao Decoction combined with fluoxetine treatment alleviates depressive symptoms in chronic stress mice by modulating intestinal microbiota[J]. J Nanjing Univ Tradit Chin Med, 2020, 36(5): 667-674. http://xb.njucm.edu.cn/article/id/zr20200515
[8]	陶伟伟, 白子君, 岳启予, 等. 栀子豉汤对慢性应激诱导的抑郁模型小鼠脑组织神经炎症和突触可塑性的影响[J]. 中医杂志, 2022, 63(11): 1073-1079. TAO W W, BAI Z J, YUE Q Y, et al. Effect of zhizichi decoction on neuroinflammation and synaptic plasticity in brain tissue of chronic stress-induced depression model mice[J]. J Tradit Chin Med, 2022, 63(11): 1073-1079.
[9]	WANG T, YAN Y F, YANG L, et al. Effects of Zuojin pill on depressive behavior and gastrointestinal function in rats with chronic unpredictable mild stress: Role of the brain-gut axis[J]. J Ethnopharmacol, 2020, 254: 112713. doi: 10.1016/j.jep.2020.112713
[10]	赵静怡, 郑金粟, 曹锐. 肝郁脾虚型功能性消化不良中医病证结合模型的研究进展[J]. 北京中医药, 2023, 42(10): 1156-1160. https://www.cnki.com.cn/Article/CJFDTOTAL-BJZO202310032.htm ZHAO J Y, ZHENG J S, CAO R. Research progress of functional dyspepsia disease and syndrome combination model with liver depression and spleen deficiency[J]. Beijing J Tradit Chin Med, 2023, 42(10): 1156-1160. https://www.cnki.com.cn/Article/CJFDTOTAL-BJZO202310032.htm
[11]	吴仁军. 越鞠丸加减治疗功能性消化不良142例[J]. 光明中医, 2014, 29(3): 519-520. doi: 10.3969/j.issn.1003-8914.2014.03.041 WU R J. 142 cases of functional dyspepsia treated by Yueju pill[J]. Guangming J Chin Med, 2014, 29(3): 519-520. doi: 10.3969/j.issn.1003-8914.2014.03.041
[12]	WU R Y, ZHU D D, XIA Y C, et al. A role of Yueju in fast-onset antidepressant action on major depressive disorder and serum BDNF expression: A randomly double-blind, fluoxetine-adjunct, placebo-controlled, pilot clinical study[J]. Neuropsychiatr Dis Treat, 2015, 11: 2013-2021.
[13]	VAUDRY D, FALLUEL-MOREL A, BOURGAULT S, et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery[J]. Pharmacol Rev, 2009, 61(3): 283-357. doi: 10.1124/pr.109.001370
[14]	李喜龙, 赵兴绪. 垂体腺苷酸环化酶激活肽的研究概况[J]. 生物化学与生物物理进展, 2001, 28(2): 140-144. https://www.cnki.com.cn/Article/CJFDTOTAL-SHSW200102002.htm LI X L, ZHAO X X. Pituitary adenylate cyclase-activating polypeptide[J]. Prog Biochem Biophys, 2001, 28(2): 140-144. https://www.cnki.com.cn/Article/CJFDTOTAL-SHSW200102002.htm
[15]	SOLES-TARRES I, CABEZAS-LLOBET N, VAUDRY D, et al. Protective effects of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide against cognitive decline in neurodegenerative diseases[J]. Front Cell Neurosci, 2020, 14: 221.
[16]	REGLODI D, ILLES A, OPPER B, et al. Presence and effects of pituitary adenylate cyclase activating polypeptide under physiological and pathological conditions in the stomach[J]. Front Endocrinol, 2018, 9: 90. doi: 10.3389/fendo.2018.00090
[17]	岳双明, 周安国, 王之盛, 等. 垂体腺苷酸环化酶激活多肽(PACAP)的研究概况[J]. 饲料工业, 2007, 28(11): 12-16. https://www.cnki.com.cn/Article/CJFDTOTAL-FEED200711004.htm YUE S M, ZHOU A G, WANG Z S, et al. Research advance of pituitary adenylate cyclase activating polypeptide[J]. Feed Ind, 2007, 28(11): 12-16. https://www.cnki.com.cn/Article/CJFDTOTAL-FEED200711004.htm
[18]	BATHINA S, DAS U N. Brain-derived neurotrophic factor and its clinical implications[J]. Arch Med Sci, 2015, 11(6): 1164-1178.
[19]	LIU S M. Neurotrophic factors in enteric physiology and pathophysiology[J]. Neurogastroenterol Motil, 2018, 30(10): e13446. doi: 10.1111/nmo.13446
[20]	LI C, CAI Y Y, YAN Z X. Brain-derived neurotrophic factor preserves intestinal mucosal barrier function and alters gut microbiota in mice[J]. Kaohsiung J Med Sci, 2018, 34(3): 134-141. doi: 10.1016/j.kjms.2017.11.002
[21]	AL-QUDAH M, ALKAHTANI R, AKBARALI H I, et al. Stimulation of synthesis and release of brain-derived neurotropic factor from intestinal smooth muscle cells by substance P and pituitary adenylate cyclase-activating peptide[J]. Neurogastroenterol Motil, 2015, 27(8): 1162-1174.
[22]	ZINK M, OTTO C, ZORNER B, et al. Reduced expression of brain-derived neurotrophic factor in mice deficient for pituitary adenylate cyclase activating polypeptide type-I-receptor[J]. Neurosci Lett, 2004, 360(1/2): 106-108.