Skip to main content

Advertisement

SpringerLink
Log in

Jiaotai Pill (交泰丸) Alleviates Insomnia through Regulating Monoamine and Organic Cation Transporters in Rats

  • Original Article
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To reveal the effect and mechanism of Jiaotai Pill (交泰丸, JTP) on insomniac rats.

Methods

The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). In behavioral experiments, rats were divided into control, insomniac model, JTP [3.3 g/(kg•d)], and diazepam [4 mg/(kg•d)] groups. The treatment effect of JTP was evaluated by weight measurement (increasement of body weight), open field test (number of crossings) and forced swimming test (immobility time). A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal, model, JTP, citalopram [30 mg/(kg•d)], maprotiline [40 mg/(kg•d)] and bupropion [40 mg/(kg•d)] groups. Expressions of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) were analyzed by quantitative polymerase chain reaction (qPCR) and Western blot in normal, model and JTP groups. A high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method was established to determine the pharmacokinetics, urine cumulative excretion of metformin in vivo, and tissue slice uptake in vitro, which were applied to assess the activity of organic cation transporters (OCTs) in hypothalamus and peripheral organs.

Results

Compared with the insomniac model group, the body weight and spontaneous locomotor were increased, and the immobility time was decreased after treatment with JTP (P<0.01). Both serotonin and dopamine contents in hypothalamus and peripheral organs were increased (P<0.01). The norepinephrine content was increased in peripheral organs and decreased in hypothalamus (P<0.05 or P<0.01). At the same time, SERT, DAT, OCT1, OCT2, and OCT3 were down-regulated in hypothalamus and peripheral organs (P<0.05). NET was down-regulated in peripheral organs and up-regulated in hypothalamus (P<0.05 or P<0.01). Moreover, the activity of OCTs in hypothalamus and peripheral organs was inhibited (P<0.05).

Conclusion

JTP alleviates insomnia through regulation of monoaminergic system and OCTs in hypothalamus and peripheral organs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chen F, Chen G, Chen Z, Zhang Z, Zhang P, Luo D, et al. Guizhi Gancao Longgu Muli Decoction for insomnia: a protocol for a systematic review. Medicine (Baltimore) 2020;99:e191–e198.

    Google Scholar 

  2. Baek JH, Nierenberg AA, Kinrys G. Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder. Aust N Z J Psychiatry 2014;48:705–715.

    Article  Google Scholar 

  3. Anafi RC, Pellegrino R, Shockley KR, Romer M, Tufik S, Pack AI. Sleep is not just for the brain: transcriptional responses to sleep in peripheral tissues. BMC Genomics 2013;14:1–19.

    Article  Google Scholar 

  4. van Neijenhof R, van Duijn E, van Den Berg JF, de Waal MWM, van der Mast RC, Comijs HC. Subjective insomnia symptoms and sleep duration are not related to hypothalamic-pituitary-adrenal axis activity in older adults. J Sleep Res 2018;27:40–46.

    Article  Google Scholar 

  5. He W, Liu G, Cai H, Sun X, Hou W, Zhang P, et al. Integrated pharmacokinetics of five protoberberine-type alkaloids in normal and insomnic rats after single and multiple oral administration of Jiao-Tai-Wan. J Ethnopharmacol 2014;154:635–644.

    Article  CAS  Google Scholar 

  6. Huang WY, Zou X, Lu FE, Zhang C, Ren YL, Xu LJ, et al. Effect of Jiaotai Pill on intestinal damage in partially sleep deprived rats. Chin J Integr Med 2017;23:901–907.

    Article  Google Scholar 

  7. Qian Z, Wang SL, Tao WW, Long HY, Wang JW. Effects of Jiaotaiwan on depressive-like behavior in mice after lipopolysaccharide administration. Metab Brain Dis 2017;32:415–426.

    Article  Google Scholar 

  8. Zou X, Huang W, Lu F, Fang K, Wang D, Zhao S, et al. The effects of Jiao-Tai-Wan on sleep, inflammation and insulin resistance in obesity-resistant rats with chronic partial sleep deprivation. BMC Complement Altern Med 2017;17:1–9.

    Article  Google Scholar 

  9. Hirotsu C, Tufik S, Andersen ML. Interactions between sleep, stress, and metabolism: from physiological to pathological conditions. Sleep Sci 2015;8:143–152.

    Article  Google Scholar 

  10. Happe S, Berger K, Investigators FS. The association of dopamine agonists with daytime sleepiness, sleep problems and quality of life in patients with Parkinson’s disease-a prospective study. J Neurol 2001;248:1062–1067.

    Article  CAS  Google Scholar 

  11. Yuan Q, Joiner WJ, Sehgal A. A sleep-promoting role for the Drosophila serotonin receptor 1A. Curr Biol 2006;16:1051–1062.

    Article  CAS  Google Scholar 

  12. Mitchell HA, Weinshenker D. Good night and good luck: norepinephrine in sleep pharmacology. Biochem Pharmacol 2010;79:801–809.

    Article  CAS  Google Scholar 

  13. Martin AM, Young RL, Leong L, Rogers GB, Spencer NJ, Jessup CF, et al. The diverse metabolic roles of peripheral serotonin. Endocrinology 2017;158:1049–1063.

    Article  CAS  Google Scholar 

  14. Eisenhofer G. The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 2001;91:35–62.

    Article  CAS  Google Scholar 

  15. El-Merahbi R, Loffler M, Mayer A, Sumara G. The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett 2015;589:1728–1734.

    Article  CAS  Google Scholar 

  16. French IT, Muthusamy KA. A review of sleep and its disorders in patients with parkinson’s disease in relation to various brain structures. Front Aging Neurosci 2016;8:1–14.

    Article  Google Scholar 

  17. Cheng MH, Bahar I. Monoamine transporters: structure, intrinsic dynamics and allosteric regulation. Nat Struct Mol Biol 2019;26:545–556.

    Article  CAS  Google Scholar 

  18. Andre P, Saubamea B, Cochois-Guegan V, Marie-Claire C, Cattelotte J, Smirnova M, et al. Transport of biogenic amine neurotransmitters at the mouse blood-retina and blood-brain barriers by uptake1 and uptake. J Cereb Blood Flow Metab 2012;32:1989–2001.

    Article  CAS  Google Scholar 

  19. Iversen L. Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 2006;147 Suppl 1:S82–S88.

    Article  CAS  Google Scholar 

  20. Bowman MA, Daws LC. Targeting serotonin transporters in the treatment of juvenile and adolescent depression. Front Neurosci 2019;13:156.

    Article  Google Scholar 

  21. Imeri L, Bianchi S, Mancia M. Muramyl dipeptide and IL-1 effects on sleep and brain temperature after inhibition of serotonin synthesis. Am J Physiol 1997;273:R1663–1668.

    CAS  PubMed  Google Scholar 

  22. Chen N, Guo CE, Chen H, Chen J, Bi X, Li H, et al. Simultaneous determination of 6 coptis alkaloids in urine and feces by LC-MS/MS and its application to excretion kinetics and the compatibility mechanism of Jiao-Tai-Wan in insomniac rats. Biomed Chromatogr 2018;32:e42–e48.

    Article  Google Scholar 

  23. Gong MJ, Yue H, Zhou XY, Li CY, Wang SM, Li SW, et al. Mechanism of Jiaotai Pills in the intervention of PCPA-induced insomnia in the rats. World J Integr Tradit West Med (Chin) 2017;12:1230–1234.

    Google Scholar 

  24. Oh DR, Kim Y, Jo A, Choi EJ, Oh KN, Kim J, et al. Sedative and hypnotic effects of Vaccinium bracteatum Thunb. through the regulation of serotonegic and GABA-ergic systems: involvement of 5-HT receptor agonistic activity. Biomed Pharmacother 2019;109:2218–2227.

    Article  CAS  Google Scholar 

  25. Gao X, Bi XN, Chen JH, Li HP, Huang YF, Qi J, et al. Changes of tissue distribution of seven Coptis Alkaloids in Jiaotai Pill in diabetic rats. Central South Pharm 2018;6:749–754.

    Google Scholar 

  26. Su J, Miao Q, Miao PP, Zhao YY, Zhang YY, Chen N, et al. Pharmacokinetics and brain distribution and metabolite identification of coptisine, a protoberberine alkaloid with therapeutic potential for CNS disorders, in rats. Biol Pharm Bull 2015;38:1518–1528.

    Article  CAS  Google Scholar 

  27. Toni R. The neuroendocrine system: organization and homeostatic role. J Endocrinol Invest 2004;27:35–47.

    CAS  PubMed  Google Scholar 

  28. Asikainen M, Toppila J, Alanko L, Ward DJ, Stenberg D, Porkka-Heiskanen T. Sleep deprivation increases brain serotonin turnover in the rat. Neuroreport 1997;8:1577–1582.

    Article  CAS  Google Scholar 

  29. Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A, et al. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 2012;17:926–939.

    Article  CAS  Google Scholar 

  30. Kliman HJ, Quaratella SB, Setaro AC, Siegman EC, Subha ZT, Tal R, et al. Pathway of maternal serotonin to the human embryo and fetus. Endocrinology 2018;159:1609–1629.

    Article  CAS  Google Scholar 

  31. Daws LC. Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther 2009;121:89–99.

    Article  CAS  Google Scholar 

  32. Kim DK, Tolliver TJ, Huang SJ, Martin BJ, Andrews AM, Wichems C, et al. Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology 2005;49:798–810.

    Article  CAS  Google Scholar 

  33. Schonfeldt-Lecuona C, Kregel T, Schmidt A, Pinkhardt EH, Lauda F, Kassubek J, et al. From imaging the brain to imaging the retina: optical coherence tomography (OCT) in Schizophrenia. Schizophr Bull 2016;42:9–14.

    PubMed  Google Scholar 

  34. Tang M, Lei J, Sun X, Liu G, Zhao S. Stress-induced anhedonia correlates with lower hippocampal serotonin transporter protein expression. Brain Res 2013;1513:127–134.

    Article  CAS  Google Scholar 

  35. Xing H, Zhang X, Xing N, Qu H, Zhang K. Uncovering pharmacological mechanisms of Zhi-Zi-Hou-Po Decoction in chronic unpredictable mild stress induced rats through pharmacokinetics, monoamine neurotransmitter and neurogenesis. J Ethnopharmacol 2019;243:1–8.

    Article  Google Scholar 

  36. Kopin IJ, Rundqvist B, Friberg P, Lenders J, Goldstein DS, Eisenhofer G. Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm. Am J Physiol 1998;275:R165–R173.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China

    Zhi-hui Li, Peng-kai Ma, Zhe Zhang, Wei Zheng, Jian-hua Chen, Chang-e Guo, Ning Chen, Xin-ning Bi & Yu-jie Zhang

Authors
  1. Zhi-hui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng-kai Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun-fang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhe Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian-hua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chang-e Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ning Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xin-ning Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yu-jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Zhang YJ and Ma PK designed the study. Guo CE, Chen N, Li ZH and Bi XN carried out the experiments. Li ZH and Ma PK drafted the manuscript. Li ZH, Huang YF and Zhang Z analyzed the data. Zheng W and Chen JH involved in discussion of experiment. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yu-jie Zhang.

Ethics declarations

The authors declare that there is no actual or potential conflict of interest.

Additional information

Supported by the National Natural Science Foundation of China (No. 81673680)

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Zh., Ma, Pk., Huang, Yf. et al. Jiaotai Pill (交泰丸) Alleviates Insomnia through Regulating Monoamine and Organic Cation Transporters in Rats. Chin. J. Integr. Med. 27, 183–191 (2021). https://doi.org/10.1007/s11655-021-3284-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-021-3284-y

Keywords

Search

Navigation