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Sini powder (四逆散) decoction alleviates mood disorder of insomnia by regulating cation-chloride cotransporters in hippocampus

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Abstract

Objective

To investigate the mechanism of Sini Powder (四逆散) decoction (SND) in the treatment of insomnia.

Methods

The rats were randomly divided into four groups: control, model, SND-treated, and Estazolamtreated groups (n=15 in each group). Sleep deprivation (SD) rat model was established using the modifified multiple platform method for 14 h per day for 14 days, and the behavior of the rats were observed. Na-K-Cl-cotransporter (NKCC1) and K+/Cl- cotransporter (KCC2) in the hippocampus were tested by immunohistochemistry, real-time polymerase chain reaction, and western blot.

Results

SD rats displayed anxiety-like behavior, which was alleviated by SND. The protein expressions of NKCC1 and KCC2 in the hippocampus were signifificantly decreased in SD rats compared with those in control rats (P<0.05); these proteins were signifificantly increased by SND (P<0.05). The mRNA expression of KCC2 was signifificantly decreased in SD rats (0.62±0.35 vs. 2.29±0.56; P=0.044), while SND showed a tendency to increase the mRNA of KCC2 in SD rats (P>0.05). By contrast, the mRNA expression of NKCC1 was signifificantly increased in the hippocampus of SD rats (6.58±1.54 vs. 2.82±0.32; P=0.011), while SND decreased the mRNA expression of NKCC1 (6.58±1.54 vs. 2.79±0.81; P=0.016).

Conclusions

Chinese medicine SND could alleviate mood disorder of SD rats by regulating cation-chloride cotransporters, such as NKCC1 and KCC2. These fifindings would have major implications in the mechanism of SND to relieve insomnia.

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References

  1. Sateia MJ. International classification of sleep disorders-3rd ed: highlights and modifications. Chest 2014;146:1387–1394.

    Article  PubMed  Google Scholar 

  2. Tjepkema M. Insomnia. Health Rep 2005;17:9–25

    PubMed  Google Scholar 

  3. Kim K, Uchiyama M, Okawa M, Liu X, Ogihara R. An epidemiological study of insomnia among the Japanese general population. Sleep 2000;23:41–47.

    CAS  PubMed  Google Scholar 

  4. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6:97.

    Article  PubMed  Google Scholar 

  5. Taylor DJ, Lichstein KL, Durrence HH, Reidel BW, Bush AJ. Epidemiology of insomnia, depression, and anxiety. Sleep 2005;28:1457–1464.

    PubMed  Google Scholar 

  6. Pallanti S, Tofani T, Zanardelli M, Di Cesare Mannelli L, Ghelardini C. BDNF and ARTEMIN are increased in drugnaïve nondepressed GAD patients: preliminary data. Int J Psychiatry Clin Pract 2014;4:1–11.

    Google Scholar 

  7. Simkin DR, Thatcher RW, Lubar J. Quantitative EEG and neurofeedback in children and adolescents: anxiety disorders, depressive disorders, comorbid addiction and attention-deficit/hyperactivity disorder, and brain injury. Child Adolesc Psychiatr Clin N Am 2014;23:427–464.

    Article  PubMed  Google Scholar 

  8. Eisch AJ, Petrik D. Depression and hippocampal neurogenesis: a road to remission? Science 2012;6103:72–75.

    Article  Google Scholar 

  9. Zhang E, Shen J, So KF. Chinese traditional medicine and adult neurogenesis in the hippocampus. J Tradit Complement Med 2014;4:77–81.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Smith SS. The influence of streßs at puberty on mood and learning: role of thea4ßd GABAA receptor. Neuroscience 2013;26:192–213.

    Article  Google Scholar 

  11. Song Z, Huang P, Qiu L, Wu Q, Gong Q, Zhang B, et al. Decreased occipital GABA concentrations in patients with first-episode major depressive disorder: a magnetic resonance spectroscopy study. J Biomed Eng (Chin) 2012;2:233–236.

    Google Scholar 

  12. Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, et al. Alterations of GABAergic and dopaminergic systems in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. Neurochem Int 2014;74:74–83.

    Article  CAS  PubMed  Google Scholar 

  13. Wagner S, Castel M, Gainer H, Yarom Y. GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature 1997;387:598–603.

    Article  CAS  PubMed  Google Scholar 

  14. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl–co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 1999;397:251–255.

    Article  CAS  PubMed  Google Scholar 

  15. Lee H, Chen CXQ, Liu YJ. KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. Eur J Neurosci 2005;21:2593–2599.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Hebert SC, Mount DB, Gamba G. Molecular physiology of caution-coupled Cl-cotransport: the SLC12 family. Eur J Physiol 2004;447:580–593.

    Article  CAS  Google Scholar 

  17. Rojas-Fernandez CH, Chen Y. Use of ultra-low-dose ( 6 mg) doxepin for treatment of insomnia in older people. Can Pharm J 2014;147:281–289.

    Article  Google Scholar 

  18. Yi LT, Li J, Liu BB, Li CF. Screening of the antidepressantlike effect of the traditional Chinese medicinal formula Si-Ni-San and their possible mechanism of action in mice. Pharmacognosy Res 2013;5:36–42.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Li Y, Li T. Effect of Sinisan on the sleep phase of insomnia rats. Pharm Clin Chin Mater Med (Chin) 2011;3:4–5.

    Google Scholar 

  20. Huang N, Lin Y, Sha H. Clinical research of modified Sini Powder to insomnia. J New Chin Med Chin (Chin) 2013;45:39–40.

    Google Scholar 

  21. Li Y, Wu P, Ning Y, Yan X, Zhu T, Ma C, et al. Sedative and hypnotic effect of freeze-dried paeoniflorin and Sini San freeze-dried powder in pentobarbital sodium-induced mice. J Tradit Chin Med (Chin) 2014;34:184–187.

    Article  CAS  Google Scholar 

  22. Suchecki D, Tufik S. Social stability attenuates the stress in the modified multiple platform method for paradoxical sleep deprivation in the rat. Physiol Behav 2000;68:309–316.

    Article  CAS  PubMed  Google Scholar 

  23. Hiroi R, Neumaier JF. Differential effects of ovarian steroids on anxiety versus fear as measured by open field test and fear-potentiated startle. Behav Brain Res 2006;166:93–100.

    Article  CAS  PubMed  Google Scholar 

  24. Nosek K, Dennis K, Andrus BM, Ahmadiyeh N, Baum AE, et al. Context and strain-dependent behavioral response to stress. Behav Brain Funct 2008;4:23.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Paxinos GWG, Watson C, eds. The rat brain in stereotaxic coordinates. SanDiego: Academic Press; 1998.

    Google Scholar 

  26. Reimund E. The free radical flux theory of sleep. Med Hypotheses 1994;43:231–233.

    Article  CAS  PubMed  Google Scholar 

  27. Zohar D, Tzischinsky O, Epstein R, Lavie P. The effects of sleep loss on medical residents’ emotional reactions to work events: a cognitive-energy model. Sleep 2005;28:47–54.

    PubMed  Google Scholar 

  28. Vandekerckhove M, Cluydts R. The emotional brain and sleep: an intimate relationship. Sleep Med Rev 2010;14:219–226.

    Article  PubMed  Google Scholar 

  29. Baglioni C, Battagliesen G, Feige B, Spiegelhalder K, Nissen C, Voderholzer U, et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord 2011;135:10–19.

    Article  PubMed  Google Scholar 

  30. Riemann D, Spiegelhalder K, Feige B, Voderholzer U, Berger M, Perlis M, et al. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010;14:19–31.

    Article  PubMed  Google Scholar 

  31. Paunio T, Korhonen T, Hublin C, Partinen M, Koskenvuo K, Koskenvuo M, et al. Poor sleep predicts symptoms of depression and disability retirement due to depression. J Affect Disord 2014;172C:381–389.

    PubMed  Google Scholar 

  32. Matrisciano F, Nasca C, Molinaro G, Riozzi B, Scaccianoce S, Raggi MA, et al. Enhanced expression of the neuronal K+/Cl–cotransporter, KCC2, inspontaneously depressed flinders sensitive line rats. Brain Res 2010;1325:112–120.

    Article  CAS  PubMed  Google Scholar 

  33. Truitt WA, Johnson PL, Dietrich AD, Fitz SD, Shekhar A. Anxiety-like behavior is modulated by a discrete subpopulation of interneurons in the basolateral amygdale. Neuroscience 2009;160:284–294.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Zhu L, Polley N, Mathews GC. NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy Res 2008;79:201–212.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Cellot G, Cherubini E. Functional role of ambient GABA in refining neuronal circuits early in postnatal development. Front Neural Circuits 2013;7:136.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Payne JA. Functional characterization of the neuronalspecific K-Cl cotransporter: implications for [K+]o regulation. Am J Physiol 1997;273:C1516–C1525.

    CAS  PubMed  Google Scholar 

  37. Monette MY, Forbush B. Regulatory activation is accompanied by movement in the C terminus of the Na-K-Cl cotransporter (NKCC1). J Biol Chem 2012;287:2210–2220.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Darman RB, Forbush B. A regulatory locus of phosphorylation in the N terminus of the Na-K-Cl cotransporter, NKCC1. J Biol Chem 2002;277:37542–37540.

    Article  CAS  PubMed  Google Scholar 

  39. Ip YK, Hou Z, Chen XL, Ong JL, Chng YR, Ching B, et al. High brain ammonia tolerance and down-regulation of Na+:K+:2Cl- cotransporter 1b mRNA and protein expression in the brain of the Swamp Eel, Monopterus albus, exposed to environmental ammonia or terrestrial conditions. PLoS One 2013;8:e69512.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Lin FJ, Yang XS, Yang D, Zou YQ. Expression of cationchloride cotransporters KCC2 and NKCC1 in brainstem of para-chlorophenylalanine-induced acute insomniarats. at Med J China (Chin) 2013;93:1507–1511.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Beijing University of Chinese Medicine, Beijing, 100029, China

    Jing Liu  (刘 晶), Feng Li  (李 峰), Jie Ma  (马 捷), Meng Mao  (毛 萌), Feng-Zhi Wu  (吴凤芝), Yan-Yang Liu  (刘艳阳), Chen-Xia Han  (韩晨霞), Yan Liu  (刘 燕), Yue-Han Song  (宋月晗) & Zhuo-Yun Wu  (吴卓耘)

  2. Xiyuan Hospital, Chinese Academy of Chinese Medical Science, Beijing, 100091, China

    Xu-Dong Tang  (唐旭东), Feng-Yun Wang  (王凤云) & Nan Kang  (康 楠)

  3. Beijng Science and Technology Publishing Co. Ltd., Beijing, 100035, China

    Shi-Jing Bai  (白世敬)

  4. World Federation of Chinese Medicine Societies, Beijing, 100101, China

    Xin-Xue Li  (李昕雪)

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  1. Jing Liu  (刘 晶)
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Corresponding author

Correspondence to Feng Li  (李 峰).

Additional information

Supported by the Beijing Municipal Natural Science Foundation (No. 7112071), Open Project Program of Key Discipline of Beijing University of Chinese Medicine (No. 522/0100604054), Collaborative Innovation Center for Nautical Traditional Chinese Medicine (No. 522/0100604299), and Postgraduate Independent Subject of Beijing University of Chinese Medicine (No. 2013-JYB22-XS-022)

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Liu, J., Li, F., Tang, XD. et al. Sini powder (四逆散) decoction alleviates mood disorder of insomnia by regulating cation-chloride cotransporters in hippocampus. Chin. J. Integr. Med. (2015). https://doi.org/10.1007/s11655-015-2308-x

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  • DOI: https://doi.org/10.1007/s11655-015-2308-x

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