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The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics

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Abstract

Rationale

An increasing number of herbal products has been introduced to treat anxiety and depression. Gelsemium elegans Benth (G. elegans) is a well-known herbal plant in Asia. Four major alkaloids (gelsemine, koumine, gelsevirine, and gelsenicine) have been isolated from G. elegans. Recently, interest has arisen to investigate the pharmaceutical potential of G. elegans alkaloids in the context of neuropsychopharmacology.

Objectives

We investigated whether G. elegans alkaloids are capable of producing anxiolytic and antidepressant effects in mouse models. In particular, we examined whether the anxiolytic action of G. elegans alkaloids is due to the agonist effects of glycine receptor in the brain.

Methods

Two mouse models (elevated plus-maze and light–dark transition model) were used to examine potential anxiolytic effects. Forced swim test and tail suspension test were used to test the antidepressive action of G. elegans alkaloids. Moreover, we also explored the anxiolytic mechanisms of G. elegans alkaloids by intracerebroventricular administration of strychnine, an antagonist of glycine receptor, in the elevated plus-maze.

Results

Gelsemine, koumine, and gelsevirine, but not gelsenicine, exhibited potent anxiolytic effects in the two anxiety models. None of the four G. elegans alkaloids exerted antidepressant effects in the two depression models. None of G. elegans alkaloids impaired spontaneous motor activities. The intracerebroventricular administration of strychnine significantly antagonized the anxiolytic effects of gelsemine, koumine, and gelsevirine administrated subcutaneously.

Conclusions

Gelsemine, koumine, and gelsevirine could be developed as the treatment of anxiety-related disorders in human patients. Their anxiolytic mechanism may be involved in the agonist action of glycine receptor in the brain.

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Abbreviations

aCSF:

Artificial cerebrospinal fluid

ANOVA:

One-way analysis of variance

CCC:

Counter-current chromatography

DZP:

Diazepam

EPM:

Elevated plus-maze

FLU:

Fluoxetine

FST:

Forced swim test

GABAA :

Gamma aminobutyric acid A receptor

G. elegans :

Gelsemium elegans Benth

Gly-R:

Glycine receptor

GM:

Gelsemine

G. sempervirens :

Gelsemium sempervirens Ait

GS:

Gelsenicine

GV:

Gelsevirine

HSCCC:

High-speed counter-current chromatography

i.c.v.:

Intracerebroventricular

i.p.:

Intraperitoneal

KM:

Koumine

LDTM:

Light–dark transition model

LD50 :

Median lethal dose

LSD:

Least significant difference

s.c.:

Subcutaneous

STR:

Strychnine

TST:

Tail suspension test

3α,5α-THP:

Allopregnanolone

3α-HSD:

3α-Hydroxysteroid dehydrogenase

5α-DHP:

5α-Dihydroprogesterone

References

  • Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 125:141–149

    Article  PubMed  CAS  Google Scholar 

  • Boyer P (2000) Do anxiety and depression have a common pathophysiological mechanism? Acta Psychiatr Scand Suppl 102:24–29

    Article  Google Scholar 

  • Braida D, Capurro V, Zani A, Rubino T, Vigano D, Parolaro D, Sala M (2009) Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents. Br J Pharmacol 157:844–853

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Dai TJ, Zeng YM (2007) Strychnine-sensitive glycine receptors mediate the analgesic but not hypnotic effects of emulsified volatile anesthetics. Pharmacology 80:151–157

    Article  PubMed  CAS  Google Scholar 

  • Clement Y, Joubert C, Kopp C, Lepicard EM, Venault P, Misslin R, Cadot M, Chapouthier G (2007) Anxiety in mice: a principal component analysis study. Neural Plast 2007

  • Costall B, Jones B, Kelly M, Naylor R, Tomkins D (1989) Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 32:777–785

    Article  PubMed  CAS  Google Scholar 

  • Dutt V, Dhar VJ, Sharma A (2010) Antianxiety activity of Gelsemium sempervirens. Pharm Biol 48:1091–1096

    Article  PubMed  Google Scholar 

  • Eser D, Romeo E, Baghai TC, Di Michele F, Schule C, Pasini A, Zwanzger P, Padberg F, Rupprecht R (2006) Neuroactive steroids as modulators of depression and anxiety. Neuroscience 138:1041–1048

    Article  PubMed  CAS  Google Scholar 

  • Griebel G, Belzung C, Misslin R, Vogel E (1993) The free-exploratory paradigm: an effective method for measuring neophobic behaviour in mice and testing potential neophobia-reducing drugs. Behav Pharmacol 4:637–644

    Article  PubMed  CAS  Google Scholar 

  • Haller J, Alicki M (2012) Current animal models of anxiety, anxiety disorders, and anxiolytic drugs. Curr Opin Psychiatry 25:59–64

    Article  PubMed  Google Scholar 

  • Hattesohl M, Feistel B, Sievers H, Lehnfeld R, Hegger M, Winterhoff H (2008) Extracts of Valeriana officinalis L. s.l. show anxiolytic and antidepressant effects but neither sedative nor myorelaxant properties. Phytomedicine 15:2–15

    Article  PubMed  Google Scholar 

  • Holladay JW, Dewey MJ, Yoo SD (1998) Pharmacokinetics and antidepressant activity of fluoxetine in transgenic mice with elevated serum alpha-1-acid glycoprotein levels. Drug Metab Dispos 26:20–24

    PubMed  CAS  Google Scholar 

  • Huang ZY, Liu M, Shen J, Su YP, Xu Y, Yu CX (2010) The anti-chronic pain effect of gelsevirine. Chin Tradit Herb Drugs 41:2034–2037

    CAS  Google Scholar 

  • Kothari S, Minda M, Tonpay SD (2010) Anxiolytic and antidepressant activities of methanol extract of Aegle marmelos leaves in mice. Indian J Physiol Pharmacol 54:318–328

    PubMed  CAS  Google Scholar 

  • Kraft K (2011) Phytotherapy for psychosomatic diseases. MMW Fortschr Med 153:35–37

    PubMed  Google Scholar 

  • Laursen SE, Belknap JK (1986) Intracerebroventricular injections in mice. Some methodological refinements. J Pharmacol Methods 16:355–357

    Article  PubMed  CAS  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    PubMed  CAS  Google Scholar 

  • Liu M, Shen J, Liu H, Xu Y, Su YP, Yang J, Yu CX (2011) Gelsenicine from Gelsemium elegans attenuates neuropathic and inflammatory pain in mice. Biol Pharm Bull 34:1877–1880

    Article  PubMed  CAS  Google Scholar 

  • Magnani P, Conforti A, Zanolin E, Marzotto M, Bellavite P (2010) Dose–effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice. Psychopharmacology 210:533–545

    Article  PubMed  CAS  Google Scholar 

  • Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38:379–395

    Article  PubMed  CAS  Google Scholar 

  • Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V (2009) Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels. Neuropsychopharmacology 34:593–606

    Article  PubMed  CAS  Google Scholar 

  • Ossenkopp KP, Macrae LK, Teskey GC (1987) Automated multivariate measurement of spontaneous motor activity in mice: time course and reliabilities of the behavioral measures. Pharmacol Biochem Behav 27:565–568

    Article  PubMed  CAS  Google Scholar 

  • Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322

    PubMed  CAS  Google Scholar 

  • Porsolt R, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  PubMed  CAS  Google Scholar 

  • Ramos A (2008) Animal models of anxiety: do I need multiple tests? Trends Pharmacol Sci 29:493–498

    Article  PubMed  CAS  Google Scholar 

  • Rupprecht R, di Michele F, Hermann B, Ströhle A, Lancel M, Romeo E, Holsboer F (2001) Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. Brain Res Brain Res Rev 37:59–67

    Article  PubMed  CAS  Google Scholar 

  • Shen J, Su YP, Xu Y, Liu H, Liu M, Yu CX (2009) Isolation and purification of gelsenicine and gelsevirine from Gelsemium elegans by high-speed counter-current chromatography. Chin Tradit Herb Drugs 40:1392–1395

    CAS  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370

    Article  PubMed  CAS  Google Scholar 

  • Su YP, Shen J, Xu Y, Zheng M, Yu CX (2011) Preparative separation of alkaloids from Gelsemium elegans Benth. using pH-zone-refining counter-current chromatography. J Chromatogr A 1218:3695–3698

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson P, Tzavara ET, Qi H, Carruthers R, Witkin JM, Nomikos GG, Greengard P (2007) Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. J Neurosci 27:4201–4209

    Article  PubMed  CAS  Google Scholar 

  • Venard C, Boujedaini N, Belon P, Mensah-Nyagan AG, Patte-Mensah C (2008) Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine. Neuroscience 153:154–161

    Article  PubMed  CAS  Google Scholar 

  • Venard C, Boujedaini N, Mensah-Nyagan AG, Patte-Mensah C (2009) Comparative analysis of gelsemine and Gelsemium sempervirens activity on neurosteroid allopregnanolone formation in the spinal cord and limbic system. Evid Based Complement Altern Med. doi:10.1093/ecam/nep083

  • Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Qiu HQ, Liu H, Liu M, Huang ZY, Yang J, Su YP, Yu CX (2012) Effects of koumine, an alkaloid of Gelsemium elegans Benth., on inflammatory and neuropathic pain models and possible mechanism with allopregnanolone. Pharmacol Biochem Behav 101:504–514

    Article  PubMed  CAS  Google Scholar 

  • Yan HC, Cao X, Das M, Zhu XH, Gao TM (2010) Behavioral animal models of depression. Neurosci Bull 26:327–337

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81173046, No. 30973520), the Key Program of Scientific Research of Fujian Medical University (No. ZD009), and the Exploitation Program of Industrial Technology of Fujian Development and Reform Commission of China ([2009] No. 958).

Conflict of interest

All authors have no potential conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Fujian Medical University, Fuzhou, 350004, Fujian, People’s Republic of China

    Ming Liu, Hui-Hui Huang, Jian Yang, Yan-Ping Su, Hong-Wei Lin, Li-Qing Lin, Wei-Jian Liao & Chang-Xi Yu

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  1. Ming Liu
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  2. Hui-Hui Huang
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  3. Jian Yang
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  7. Wei-Jian Liao
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  8. Chang-Xi Yu
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Corresponding author

Correspondence to Chang-Xi Yu.

Additional information

Ming Liu and Hui-Hui Huang contributed equally to this work.

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ESM 1

Original data of elevated plus-maze, light–dark transition model, forced swim test, tail suspension test, spontaneous motor activity test, acute toxicity test, and strychnine antagonism test (PDF 742 kb)

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Liu, M., Huang, HH., Yang, J. et al. The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics. Psychopharmacology 225, 839–851 (2013). https://doi.org/10.1007/s00213-012-2867-x

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