水合橙皮内酯通过调节胃饥饿素和神经回路发挥抗抑郁促动力作用

LIU Ya-lin; XU Jian-jun; HAN Lin-ran; LIU Xiang-fei; LIN Mu-hai; WANG Yun; XIAO Zhe; HUANG Yun-ke; REN Ping; HUANG Xi

doi:10.1007/s11655-022-3308-2

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水合橙皮内酯通过调节胃饥饿素和神经回路发挥抗抑郁促动力作用

Original Article | Updated：2023-05-25

- 水合橙皮内酯通过调节胃饥饿素和神经回路发挥抗抑郁促动力作用
- Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry
- 中国结合医学杂志（英文版） 2023年29卷第6期页码：490-499
- Affiliations：
  
  1.Institute of Traditional Chinese Medicine-Related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing(210023), China
  2.School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou (450046), China
  3.Department of Outpatient, Xuzhou Central Hospital, Xuzhou, Shangdong Province (221000), China
  4.Department of Obstetrics and Gynecology, Women's Hospital School of Medicine, Zhejiang University, Hangzhou (310006), China
  5.Department of Geriatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing (210023), China
- Author bio：
  
  Prof. HUANG Xi, E-mail: tcmhuangx59@163.com
- Funds：
  
  National Natural Science Foundation of China(81573797;81973589;81072967);the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)
- DOI：10.1007/s11655-022-3308-2
  中图分类号：
- 纸质出版日期：2023-06，
  
  网络出版日期：2022-07-26，
  
  录用日期：2021-03-21
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水合橙皮内酯通过调节胃饥饿素和神经回路发挥抗抑郁促动力作用[J]. 中国结合医学杂志（英文版）, 2023,29(6):490-499.

LIU Ya-lin, XU Jian-jun, HAN Lin-ran, et al. Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry[J]. Chinese Journal of Integrative Medicine, 2023,29(6):490-499.
水合橙皮内酯通过调节胃饥饿素和神经回路发挥抗抑郁促动力作用[J]. 中国结合医学杂志（英文版）, 2023,29(6):490-499. DOI： 10.1007/s11655-022-3308-2.

LIU Ya-lin, XU Jian-jun, HAN Lin-ran, et al. Meranzin Hydrate Improves Depression-Like Behaviors and Hypomotility via Ghrelin and Neurocircuitry[J]. Chinese Journal of Integrative Medicine, 2023,29(6):490-499. DOI： 10.1007/s11655-022-3308-2.

摘要

目的

研究柴胡疏肝散(CSP)及其吸收有效活性成分水合橙皮内酯(MH)的抗抑郁和促胃肠动力作用及其潜在的共享机制.

方法

通过随机数字表法将120只SD大鼠随机分为空白组、模型组、氟西汀组(20 mg/kg)、莫沙必利组(10 mg/kg)、CSP组(30 g/kg)、MH组(9.18 mg/kg)、拮抗剂[D-Lys3]-GHRP-6组(0.5 mg/kg)和(MH+[D-Lys3]-GHRP-6)组

每组8只. 将32只小鼠随机分为野生型组、MH(18 mg/kg)组、生长激素促泌素受体基因敲除组(GHSR-KO)、GHSR+MH组

每组8只. 采用强迫游泳实验(FST)、旷场实验(OFT)、悬尾实验(TST)、胃排空实验(GE)和肠推进实验(IT)在单次给药30分钟后评价SD大鼠和小鼠的抗抑郁和促胃肠动力(A&P)作用. 通过蛋白免疫印迹法(Western blot) 检测大鼠海马中脑源性神经营养因子(BDNF)和磷酸化雷帕霉素靶蛋白(p-mTOR)的表达情况. 采用7.0血氧水平依赖功能磁共振成像技术(fMRI-BOLD)

观察药物干预前后脑区变化.

结果

在急性强迫游泳应急大鼠中

MH灌胃治疗发挥了与母方CSP类似的抗抑郁(FST

OFT)和促胃肠动力(GE

IT)作用(

0.05); 拮抗剂[D-Lys3]-GHRP-6可抑制MH对FST和GE的调节作用(

0.05). 同样

MH灌胃治疗也缓解了野生型小鼠的抑郁样行为(FST、TST)

对GHSR-KO小鼠中MH无效. 此外

MH干预可显著增加急性应激大鼠海马BDNF及p-mTOR蛋白表达(

0.01)

其效果可被[D-Lys3]-GHRP-6抑制(

0.01). 急性应激大鼠脑区血氧水平变化主要与海马-丘脑-基底节(HTB)神经回路相关

[D-Lys3]-GHRP-6也同步抑制HTB脑区血氧水平表达

促胃肠动力药物莫沙必利仅对丘脑和基底节有作用

对海马无作用效果.

结论

MH可通过共享调节胃饥饿素和脑区BOLD信号表达

发挥类似于母方CSP的抗抑郁和促动力作用. 与急性应激、干预和共享调节三者密切相关的HTB神经回路突出了抗抑郁的统一理论.

Abstract

Objective:

To investigate whether meranzin hydrate (MH) can alleviate depression-like behavior and hypomotility similar to Chaihu Shugan Powder (CSP)

and further explore the potential common mechanisms.

Methods:

Totally 120 Spraque-Dawley rats were randomly divided into 5–8 groups including sham

vehicle

fluoxetine (20 mg/kg)

mosapride (10 mg/kg)

CSP (30 g/kg)

MH (9.18 mg/kg)

[D-Lys3]-GHRP-6 (Dlys

0.5 mg/kg)

and MH+Dlys groups by a random number table

8 rats in each group. And 32 mice were randomly divided into wild-type

MH (18 mg/kg)

growth hormone secretagogue receptor-knockout (GHSR-KO)

and GHSR+MH groups

8 mice in each group. The forced swimming test (FST)

open field test (OFT)

tail suspension test (TST)

gastric emptying (GE) test

and intestinal transit (IT) test were used to assess antidepressant and prokinetic (AP) effects after drug single administration for 30 min with absorbable identification in rats and mice

respectively. The protein expression levels of brain-derived neurotrophic factor (BDNF) and phosphorylated mammalian target of rapamycin (p-mTOR) in the hippocampus of rats were evaluated by Western blot. The differences in functional brain changes were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD).

Results:

MH treatment improved depression-like behavior (FST

OFT) and hypomotility (GE

IT) in the acute forced swimming (FS) rats (all

0.05)

and the effects are similar to the parent formula CSP. The ghrelin antagonist [D-Lys3]-GHRP-6 inhibited the effect of MH on FST and GE (

0.05). Similarly

MH treatment also alleviated depression-like behavior (FST

TST) in the wild-type mice

however

no effects were found in the GHSR KO mice. Additionally

administration of MH significantly stimulated BDNF and p-mTOR protein expressions in the hippocampus (both

0.01)

which were also prevented by [D-Lys3]-GHRP-6 (

0.01). Besides

3 main BOLD foci following acute FS rats implicated activity in hippocampus–thalamus–basal ganglia (HTB) circuits. The [D-Lys3]-GHRP-6 synchronously inhibited BOLD HTB foci. As expected

prokinetic mosapride only had effects on the thalamus and basal ganglia

but not on the hippocampus. Within the HTB

the hippocampus is implicated in depression and FD.

Conclusions:

MH accounts for part of AP effects of parent formula CSP in acute FS rats

mainly via ghrelin-related shared regulation coupled to BOLD signals in brain areas. This novel functionally connection of HTB following acute stress

treatment

and regulation highlights anti-depression unified theory.

关键词

Keywords

Chinese medicineGan (Liver) governing free flow of qicomorbiditydepressionhypomotilityghrelinblood oxygen level-dependent

references

Ledford H. If depression were cancer. Nature 2014; 515:182-184.

Mahadeva S, Ford AC. Clinical and epidemiological differences in functional dyspepsia between the East and the West. Neurogastroenterol Motil 2016; 28:167-174.

Afridi MI, Siddiqui MA, Ansari A. Gastrointestinal somatization in males and females with depressive disorder. J Pak Med Associat 2009; 59:675-659.

Jamil O, Sarwar S, Hussain Z, Fiaz RO, Chaudary RD. Association between functional dyspepsia and severity of depression. J Coll Phys Surg Pak 2016; 26:513-516.

Adibi P, Keshteli AH, Daghaghzadeh H, Roohafza H, Pournaghshband N, Afshar H. Association of anxiety, depression, and psychological distress in people with and without functional dyspepsia. Adv Biomed Res 2016; 5:195.

Monteggia LM. Put therapies first. Nature 2014; 515:200.

Chancellor D. The depression markets. Nat Rev Drug Discov 2011; 10:809-810.

Glynn LG. Multimorbidity: another key issue for cardiovascular medicine. Lancet 2009; 374:1421-1422.

Fujitsuka N, Asakawa A, Hayashi M, Sameshima M, Amitani H, Kojima S, et al. Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin. Biol Psychiatry 2009; 65:748-759.

Schatzberg AF. Development of new psychopharmacological agents for depression and anxiety. Psychiatr Clin North Am 2015; 38:379-393.

Schatzberg AF. Issues encountered in recent attempts to develop novel antidepressant agents. Ann N Y Acad Sci 2015; 1345:67-73.

Reardon S. Party drug's power to fight depression puzzles scientists. Nature 2017; 545:17.

Ingram J, Taylor H, Churchill C, Pike A, Greenwood R. Metoclopramide or domperidone for increasing maternal breast milk output: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2012; 97: F241-F245.

Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World Psychiatry 2010; 9:155-161.

Zhang Y, Huang X, Wang Y, Xie Y, Qiu X, Ren P, et al. Ferulic acid-induced anti-depression and prokinetics similar to Chaihu-Shugan-San via polypharmacology. Brain Res Bull 2011; 86:222-228.

Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ. The brain-gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut 2012; 61:1284-1290.

Yang N, Jiang X, Qiu X, Hu Z, Wang L, Song M. Modified Chaihu Shugan Powder for functional dyspepsia: meta-analysis for randomized controlled trial. Evid-Based Complement Alternat Med 2013; 2013:791724.

Xie Y, Huang X, Hu SY, Zhang YJ, Wang Y, Qiu XJ, et al. The involvement of AMPA-ERK1/2-BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate. Amino Acids 2013; 44:413-422.

Shi S, Yan H, Chen Y, Liu Y, Zhang X, Xie Y, et al. Pharmacokinetic study of precisely representative antidepressant, prokinetic, anti-inflammatory and anti-oxidative compounds from Fructus aurantii and Magnolia Bark. Chem Biol Interact 2020; 315:108851.

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12:453-466.

Stevens BR, Goel R, Seungbum K, Richards EM, Holbert RC, Pepine CJ, et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut 2018; 67:1555-1557.

Roze C. Neurohumoral control of gastrointestinal motility. Reprod Nutr Dev 1980; 20:1125-1141.

Wilhelmsen I. Brain-gut axis as an example of the bio-psycho-social model. Gut 2000; 47 Suppl 4: Ⅳ5-7; discussion Ⅳ10.

Drossman DA, Tack J, Ford AC, Szigethy E, Tornblom H, van Oudenhove L. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation working team report. Gastroenterology 2018; 154:1140-1171.e1.

Huang W, Heffernan ME, Li Z, Zhang N, Overstreet DH, King JA. Fear induced neuronal alterations in a genetic model of depression: an fMRI study on awake animals. Neurosci Lett 2011; 489:74-78.

Press J. Metapsychological and clinical issues in psychosomatics research. Int J Psychoanal 2016; 97:89-113.

Perez-Cervera L, Carames JM, Fernandez-Molla LM, Moreno A, Fernandez B, Perez-Montoyo E, et al. Mapping functional connectivity in the rodent brain using electric-stimulation fMRI. Methods Mol Biol 2018; 1718:117-134.

Nr S, Gf K. Dopamine, schizophrenia, mania, and depression: toward a unified hypothesis of cortico-striatopallido-thalamic function. Behav Brain Sci 1987; 10:197-245.

Grandjean J, Azzinnari D, Seuwen A, Sigrist H, Seifritz E, Pryce CR, et al. Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression. Neuroimage 2016; 142:544-552.

Lohani S, Poplawsky AJ, Kim SG, Moghaddam B. Unexpected global impact of VTA dopamine neuron activation as measured by opto-fMRI. Mol Psychiatry 2017; 22:585-594.

Musazzi L, Tornese P, Sala N, Popoli M. Acute or chronic?A stressful question. Trends Neurosci 2017; 40:525-535.

Siero JC, Hermes D, Hoogduin H, Luijten PR, Ramsey NF, Petridou N. BOLD matches neuronal activity at the mm scale: a combined 7T fMRI and ECoG study in human sensorimotor cortex. Neuroimage 2014; 101:177-184.

Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology 2006; 131:1925-1942.

Zhou T, Zhu H, Fan Z, Wang F, Chen Y, Liang H, et al. History of winning remodels thalamo-PFC circuit to reinforce social dominance. Science 2017; 357:162-168.

Hampton T. Organoids reveal clues to gut-brain communication. JAMA 2017; 318:787-788.

Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab 2015; 4:437-460.

Xie Y, Huang X, Hu SY, Qiu XJ, Zhang YJ, Ren P, et al. Meranzin hydrate exhibits anti-depressive and prokinetic-like effects through regulation of the shared alpha2-adrenoceptor in the brain-gut axis of rats in the forced swimming test. Neuropharmacology 2013; 67:318-325.

Bogdanova OV, Kanekar S, D'Anci KE, Renshaw PF. Factors influencing behavior in the forced swim test. Physiol Behav 2013; 118:227-39.

Powell TR, Fernandes C, Schalkwyk LC. Depression-related behavioral tests. Curr Protoc Mouse Biol 2012; 2:119-127.

De Winter BY, Bredenoord AJ, De Man JG, Moreels TG, Herman AG, Pelckmans PA. Effect of inhibition of inducible nitric oxide synthase and guanylyl cyclase on endotoxin-induced delay in gastric emptying and intestinal transit in mice. Shock 2002; 18:125-131.

De Winter BY, De Man JG, Seerden TC, Depoortere I, Herman AG, Peeters TL, et al. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterol Motil 2004; 16:439-446.

Nie B, Hui J, Wang L, Chai P, Gao J, Liu S, et al. Automatic method for tracing regions of interest in rat brain magnetic resonance imaging studies. J Magn Reson Imag 2010; 32:830-835.

Nie B, Chen K, Zhao S, Liu J, Gu X, Yao Q, et al. A rat brain MRI template with digital stereotaxic atlas of fine anatomical delineations in paxinos space and its automated application in voxel-wise analysis. Hum Brain Map 2013; 34:1306-1318.

Nie B, Liu H, Chen K, Jiang X, Shan B. A statistical parametric mapping toolbox used for voxel-wise analysis of FDG-PET images of rat brain. PLoS One 2014; 9: e108295.

Chen M, Men L, Ou L, Li T, Li M, Zhong X, et al. Effectiveness and safety of modified 'Huoxue Shugan' formulas on coronary heart disease combined with depression: protocol for a systematic review. BMJ Open 2018; 8: e022868.

Wang Y, Fan R, Huang X. Meta-analysis of the clinical effectiveness of traditional Chinese medicine formula Chaihu-Shugan-San in depression. J Ethnopharmacol 2012; 141: 571-577.

Tomita T, Oshima T, Miwa H. New approaches to diagnosis and treatment of functional dyspepsia. Curr Gastroenterol Rep 2018; 20:55.

Kim SY, Choi CB, Lee HS, Lee SH, Woo DC, Kim HY, et al. Reversal of myo-inositol metabolic level in the left dorsolateral prefrontal cortex of rats exposed to forced swimming test following desipramine treatment: an in vivo localized (1) H-MRS study at 4.7 T. Magn Reson Imag 2010; 28:1461-1467.

Gao L, Huang P, Dong Z, Gao T, Huang S, Zhou C, et al. Modified Xiaoyaosan (MXYS) exerts anti-depressive effects by rectifying the brain blood oxygen level-dependent fMRI signals and improving hippocampal neurogenesis in mice. Front Pharmacol 2018; 9:1098.

Hubbard CS, Karpowicz JM, Furman AJ, Da SJ, Seminowicz DA, Traub RJ. Estrogen-dependent visceral hypersensitivity following stress in rats: an fMRI study. Mol Pain 2016; 12:12/0/1744806916654145.

Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402:656-660.

Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 2008; 11:752-753.

Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature 2011; 475:91-95.

Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:140-144.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329:959-964.

Nunes D, Ianus A, Shemesh N. Layer-specific connectivity revealed by diffusion-weighted functional MRI in the rat thalamocortical pathway. Neuroimage 2019; 184:646-657.

Harmer J, Sanchez-Panchuelo RM, Bowtell R, Francis ST. Spatial location and strength of BOLD activation in high-spatial-resolution fMRI of the motor cortex: a comparison of spin echo and gradient echo fMRI at 7 T. NMR Biomed 2012; 25:717-725.

Hirvonen J, Hietala J, Kajander J, Markkula J, Rasi-Hakala H, Salminen JK, et al. Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with [11C]raclopride PET. J Psychopharmacol 2011; 25:1329-1336.

Zhang Y, Liu F, Xiao H, Yao X, Li G, Choi SR, et al. Fluorine-18 labeled diphenyl sulfide derivatives for imaging serotonin transporter (SERT) in the brain. Nucl Med Biol 2018; 66:1-9.

Liu P, Zeng F, Yang F, Wang J, Liu X, Wang Q, et al. Altered structural covariance of the striatum in functional dyspepsia patients. Neurogastroenterol Motil 2014; 26:1144-1154.

Lee IS, Wang H, Chae Y, Preissl H, Enck P. Functional neuroimaging studies in functional dyspepsia patients: a systematic review. Neurogastroenterol Motil 2016; 28:793-805.

Jones RB, Mckie S, Astbury N, Little TJ, Tivey S, Lassman DJ, et al. Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid. Gut 2012; 61:1543-1551.

Li J, An R, Zhang Y, Li X, Wang S. Correlations of macronutrient-induced functional magnetic resonance imaging signal changes in human brain and gut hormone responses. Am J Clin Nutr 2012; 96:275-282.

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