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Koumine exhibits anxiolytic properties without inducing adverse neurological effects on functional observation battery, open-field and Vogel conflict tests in rodents

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Abstract

Koumine, an active alkaloid of neurotoxic plant Gelsemium, has been focused on its therapeutic uses, especially in central nervous system. Nevertheless, less is known about the neurological effects of koumine, which hampers its potential therapeutic exploitation. Moreover, as the anxiolytic potential of Gelsemium has raised many critical issues, its active principles on the anxiolytic and other neurological effects need to be further investigated. Here, we used functional observation battery (FOB) of mice to systematically measure the neurological effects of koumine at the effective doses, and then further confirmed its anxiolytic properties in open-field test (OFT) of mice and Vogel conflict test (VCT) of rats. Koumine exhibited anxiolytic-like activities but did not affect other autonomic, neurological and physical functions in FOB. Furthermore, koumine released anxiolytic responses and anti-punishment action in a manner similar to diazepam in OFT and VCT, respectively. The results constitutes solid set of fundamental data further demonstrating anxiolytic properties of koumine at the therapeutic doses without inducing adverse neurological effects, which supports the perspectives for the development of safe and effective koumine medicine against pathological anxiety.

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Abbreviations

KM:

Koumine

DZP:

Diazepam

MP:

Morphine

FOB:

Functional observation battery

OFT:

Open field test

VCT:

Vogel conflict test

i.p.:

Intraperitoneally

i.g.:

Intragastrically

s.c.:

Subcutaneously

i.v.:

Intravenously

References

  1. Rujjanawate C, Kanjanapothi D, Panthong A (2003) Pharmacological effect and toxicity of alkaloids from Gelsemium elegans Benth. J Ethnopharmacol 89:91–95

    Article  CAS  PubMed  Google Scholar 

  2. Jin GL, Su YP, Liu M, Xu Y, Yang J, Liao KJ, Yu CX (2014) Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)−a review of their phytochemistry, pharmacology, toxicology and traditional use. J Ethnopharmacol 152:33–52

    Article  CAS  PubMed  Google Scholar 

  3. Zhang JY, Wang YX (2015) Gelsemium analgesia and the spinal glycine receptor/allopregnanolone pathway. Fitoterapia 100:35–43

    Article  CAS  PubMed  Google Scholar 

  4. Chou TQ (1931) The Alkaloids of Gelsemium I. Gelsemine and Gelsemicine. Chin J Phys 5:131–140

    CAS  Google Scholar 

  5. Kitajima M (2007) Chemical studies on monoterpenoid indole alkaloids from medicinal plant resources Gelsemium and Ophiorrhiza. J Nat Med 61:14–23

    Article  CAS  Google Scholar 

  6. Chou TQ (1931) The alkaloids of Chinese Gelsemium Kou-Wen Gelsemium elegans Bth. Chin J Phys 5:345–352

    CAS  Google Scholar 

  7. Chou TQ (1936) The alkaloids of Chinese Gelsemium Ta-Cha-Yen. Chin J Phys 10:79–84

    CAS  Google Scholar 

  8. Fang L, Zhou J, Lin Y, Wang X, Sun Q, Li JL, Huang L (2013) Large-scale separation of alkaloids from Gelsemium elegans by pH-zone-refining counter-current chromatography with a new solvent system screening method. J Chromatogr A 1307:80–85

    Article  CAS  PubMed  Google Scholar 

  9. Chen WL, Yang Y, Wu SS (2011) Determination the content of koumine, gelsemine and humantenmine in Fujian Gelsemium elegant. J Fujian Univ TCM 21:48–50

    Google Scholar 

  10. Zhang X, Chen Y, Gao B, Luo D, Wen Y, Ma X (2015) Apoptotic effect of koumine on human breast cancer cells and the mechanism involved. Cell Biochem Biophys 72:411–416

    Article  CAS  PubMed  Google Scholar 

  11. Zhang L, Huang C, Zhang Z, Wang Z, Lin J (2005) Therapeutic effects of koumine on psoriasis: an experimental study in mice. J First Mil Univ 25:547–549

    Google Scholar 

  12. Cai J, Wang W, Lei L, Chi D (2007) An experimental study on anti-stress effect of koumine on mice. J Guangzhou Univ Tradit Chin Med 24:317–319

    CAS  Google Scholar 

  13. Ling Q, Liu M, Wu M, Xu Y, Yang J, Huang HH, Yu CX (2014) Anti-allodynic and neuroprotective effects of koumine, a Benth alkaloid, in a rat model of diabetic neuropathy. Biol Pharm Bull 37:858–864

    Article  CAS  PubMed  Google Scholar 

  14. Qiu HQ, Xu Y, Jin GL, Yang J, Liu M, Li S, Yu CX (2015) Koumine enhances spinal cord 3alpha-hydroxysteroid oxidoreductase expression and activity in a rat model of neuropathic pain. Mol Pain 11:46

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xu Y, Qiu HQ, Liu H, Liu M, Huang Z, Yang J, Su Y, 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  CAS  PubMed  Google Scholar 

  16. Liu M, Huang HH, Yang J, Su Y, Lin H, Lin L, Liao W, Yu CX (2013) The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics. Psychopharmacology 225:839–851

    Article  CAS  PubMed  Google Scholar 

  17. Huang HH, Liu M, Chen C, Yu CX (2014) Effects of koumine on the behavior of rat in elevated plus maze. Northwest Pharm J 26:839–851

    Google Scholar 

  18. Bellavite P, Magnani P, Zanolin E, Conforti A (2011) Homeopathic doses of Gelsemium sempervirens improve the behavior of mice in response to novel environments. Evid Based Complement Altern Med. doi:10.1093/ecam/nep139

    Google Scholar 

  19. Bousta D, Soulimani R, Jarmouni I, Belon P, Falla J, Froment N, Younos C (2001) Neurotropic, immunological and gastric effects of low doses of Atropa belladonna L., Gelsemium sempervirens L. and Poumon histamine in stressed mice. J Ethnopharmacol 74:205–215

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  21. 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  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bellavite P, Magnani P, Marzotto M, Conforti A (2009) Assays of homeopathic remedies in rodent behavioural and psychopathological models. Homeopathy 98:208–227

    Article  PubMed  Google Scholar 

  23. Bellavite P, Magnani P, Conforti A, Marzotto M, Zanolin M (2011) Response to a comment by Luigi Cervo and Valter Torri on: “Dose–effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice” (Magnani P, et al, Psychopharmacology, 2010). Psychopharmacology 220:441–442

    Article  PubMed Central  Google Scholar 

  24. Cervo L, Torri V (2012) Comment on:“Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice” (Magnani P, Conforti A, Zanolin E, Marzotto M and Bellavite P, Psychopharmacology, 2010). Psychopharmacology 220:439–440

    Article  CAS  PubMed  Google Scholar 

  25. Chirumbolo S (2011) Gelsemine and Gelsemium sempervirens L. Extracts in animal behavioral test: comments and related biases. Front Neurol 2:31

    PubMed  PubMed Central  Google Scholar 

  26. Chirumbolo S (2012) Plant-derived extracts in the neuroscience of anxiety on animal models: biases and comments. Int J Neurosci 122:177–188

    Article  PubMed  Google Scholar 

  27. Chirumbolo S (2015) On Gelsemium and complementary and alternative medicine (CAM) in anxiety and experimental neurology. Neurol Ther 4:1–10

    Article  PubMed  Google Scholar 

  28. Paris A, Schmidlin S, Mouret S, Hodaj E, Marijnen P, Boujedaini N, Polosan M, Cracowski JL (2012) Effect of Gelsemium 5CH and 15CH on anticipatory anxiety: a phase III, single-centre, randomized, placebo-controlled study. Fundam Clin Pharmacol 26:751–760

    Article  CAS  PubMed  Google Scholar 

  29. Cryan JF, Sweeney FF (2011) The age of anxiety: role of animal models of anxiolytic action in drug discovery. Br J Pharmacol 164:1129–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moser VC (2011) Functional assays for neurotoxicity testing. Toxicol Pathol 39:36–45

    Article  PubMed  Google Scholar 

  31. Moser VC, McDaniel KL, Phillips PM (1991) Rat strain and stock comparisons using a functional observational battery: baseline values and effects of amitraz. Toxicol Appl Pharmacol 108:267–283

    Article  CAS  PubMed  Google Scholar 

  32. 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  CAS  PubMed  Google Scholar 

  33. Brain PF, Nowell NW (1969) Some behavioral and endocrine relationships in adult male laboratory mice subjected to open field and aggression tests. Physiol Behav 4:945–947

    Article  Google Scholar 

  34. Marusich JA, Grant KR, Blough BE, Wiley JL (2012) Effects of synthetic cathinones contained in “Bath Salts” on motor behavior and a functional observational battery in mice. Neurotoxicology 33:1305–1313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moscardo E, Maurin A, Dorigatti R, Champeroux P, Richard S (2007) An optimised methodology for the neurobehavioural assessment in rodents. J Pharmacol Toxicol Methods 56:239–255

    Article  CAS  PubMed  Google Scholar 

  36. Redfern WS, Strang I, Storey S, Heys C, Barnard C, Lawton K, Hammond TG, Valentin JP (2005) Spectrum of effects detected in the rat functional observational battery following oral administration of non-CNS targeted compounds. J Pharmacol Toxicol Methods 52:77–82

    Article  CAS  PubMed  Google Scholar 

  37. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  38. Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1–7

    Article  CAS  PubMed  Google Scholar 

  39. Moreira FA, Aguiar D, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–1471

    Article  CAS  PubMed  Google Scholar 

  40. Jastrzebska-Wiesek M, Siwek A, Partyka A, Kubacka M, Mogilski S, Wasik A, Kolaczkowski M, Wesolowska A (2014) Pharmacological evaluation of the anxiolytic-like effects of EMD 386088, a partial 5-HT6 receptor agonist, in the rat elevated plus-maze and Vogel conflict tests. Neuropharmacology 85:253–262

    Article  CAS  PubMed  Google Scholar 

  41. Menendez L, Lastra A, Hidalgo A, Baamonde A (2002) Unilateral hot plate test: a simple and sensitive method for detecting central and peripheral hyperalgesia in mice. J Neurosci Methods 113:91–97

    Article  CAS  PubMed  Google Scholar 

  42. Denenberg VH (1969) Open-field bheavior in the rat: what does it mean? Ann N Y Acad Sci 159:852–859

    Article  CAS  PubMed  Google Scholar 

  43. Brunner SM, Farzi A, Locker F, Holub BS, Drexel M, Reichmann F, Lang AA, Mayr JA, Vilches JJ, Navarro X, Lang R, Sperk G, Holzer P, Kofler B (2014) GAL3 receptor KO mice exhibit an anxiety-like phenotype. Proc Natl Acad Sci USA 111:7138–7143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chi DB, Lei LS, Yang HX, Sun LS (2004) General pharmacology of koumine parenteral solution. J First Mil Med Univ 24:32–34

    CAS  Google Scholar 

  45. Chen CJ, Xin ZM, Lin J, Zhang SH, Ye LX, Su YP, Yu CX (2014) Effect of koumine on spontaneous locomotor, coordinated locomotor and subthreshold-dose barbital-induced hypnosis in mice. Fujian Med Univ 48:13–15

    Google Scholar 

  46. Rogers DC, Jones DN, Nelson PR, Jones CM, Quilter CA, Robinson TL, Hagan JJ (1999) Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res 105:207–217

    Article  CAS  PubMed  Google Scholar 

  47. Treit D, Fundytus M (1988) Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav 31:959–962

    Article  PubMed  Google Scholar 

  48. Choleris E, Thomas AW, Kavaliers M, Prato FS (2001) A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev 25:235–260

    Article  CAS  PubMed  Google Scholar 

  49. Millan MJ, Brocco M (2003) The Vogel conflict test: procedural aspects, gamma-aminobutyric acid, glutamate and monoamines. Eur J Pharmacol 463:67–96

    Article  CAS  PubMed  Google Scholar 

  50. Ohl F (2005) Animal models of anxiety. In: Ströhle A (ed) Handbook of experimental pharmacology. Springer, Berlin, pp 35–69

    Google Scholar 

  51. Crawley J (1999) Evaluating anxiety in rodents. In: Crusio W, Gerlai R (eds) Handbook of molecular genetic techniques for brain and behavior research. Techniques in the behavioral and neural sciences. Elsevier, Amsterdam, pp 667–673

    Chapter  Google Scholar 

  52. Culpepper L (2002) Generalized anxiety disorder in primary care: emerging issues in management and treatment. J Clin Psychiatry 63:35–42

    PubMed  Google Scholar 

  53. Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J (2002) Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry 63:24–34

    PubMed  Google Scholar 

  54. Du XB, Dai YH, Zhang CL, Lu SL, Liu ZG (1982) Study on gelsemium alkaloids—I. Structure of gelsenicine. Acta Chim Sinica 40:1137–1141

    CAS  Google Scholar 

  55. Zhou YP, Xu W, Chen XY (1995) Toxicity and respiratory inhibition of humantenmine. Chin J Pharmacol Toxicity 9:69–72

    CAS  Google Scholar 

  56. Chou TQ (1931) The Toxicity of Gelsemium. Exp Biol Med (Maywood) 28:789–790

    Article  Google Scholar 

  57. Boyer P (2000) Do anxiety and depression have a common pathophysiological mechanism? Acta Psychiatr Scand (Suppl) 406:24–29

    Article  Google Scholar 

  58. Faravelli C, Lo Sauro C, Lelli L, Pietrini F, Lazzeretti L, Godini L, Benni L, Fioravanti G, Talamba GA, Castellini G, Ricca V (2012) The role of life events and HPA axis in anxiety disorders: a review. Curr Pharm Des 18:5663–5674

    Article  CAS  PubMed  Google Scholar 

  59. Dallman MF, Akana SF, Levin N, Walker CD, Bradbury MJ, Suemaru S, Scribner KS (1994) Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. Ann N Y Acad Sci 746:22–31

    Article  CAS  PubMed  Google Scholar 

  60. Schule C, Nothdurfter C, Rupprecht R (2014) The role of allopregnanolone in depression and anxiety. Prog Neurobiol 113:79–87

    Article  PubMed  Google Scholar 

  61. Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D (2015) GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response. Front Neuroendocrinol 36:28–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Venard C, Boujedaini N, Mensah-Nyagan AG, Patte-Mensah C (2011) 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

    Google Scholar 

  63. Zhang JY, Gong N, Huang JL, Guo LC, Wang YX (2013) Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal alpha3 glycine receptors. Pain 154:2452–2462

    Article  CAS  PubMed  Google Scholar 

  64. 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  CAS  PubMed  Google Scholar 

  65. Chen CJ, Zhong ZF, Xie X, Chen HZ, Yu CX (2016) Discussion on the anxiolytic effect of koumine for the isolated rats and its mechanism. China Med Herald 13:8–12

    Article  Google Scholar 

  66. Zhong ZF, Chen CJ, Xu Y, Yu CX (2016) The anxiolytic effects of koumine and its mechanisms associated with neurosteroids and HPA axis. Chin J Pharm Toxicol 30:482

    Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81302756), the Research Fund for the Doctoral Program of Higher Education of China (No. 20133518110004), the Natural Science Foundation of Fujian Province of China (No. 2013J05118) and the Ph.D. Programs Foundation of Fujian Medicine University (No. 2011bs003). We would like to thank Ming Liu and Gui-Lin Jin for their assistance.

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Correspondence to Chang-Xi Yu.

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Chen, CJ., Zhong, ZF., Xin, ZM. et al. Koumine exhibits anxiolytic properties without inducing adverse neurological effects on functional observation battery, open-field and Vogel conflict tests in rodents. J Nat Med 71, 397–408 (2017). https://doi.org/10.1007/s11418-017-1070-0

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