Neurochemical Research

, Volume 42, Issue 2, pp 678–685 | Cite as

Antidepressant-Like Effect of Isorhynchophylline in Mice

  • Yan-Fang Xian
  • Ding Fan
  • Siu-Po Ip
  • Qing-Qiu Mao
  • Zhi-Xiu Lin
Original Paper


Isorhynchophylline (IRN), an oxindole alkaloid, has been identified as the main active ingredient responsible for the biological activities of Uncaria rhynchophylla (Miq) Miq ex Havil. (Rubiaceae). Previous studies in our laboratory have revealed that IRN possesses potent neuroprotective effects in different models of Alzheimer’s disease. However, the antidepressant-like effects of IRN are remained unclear. The present study aims to evaluate the antidepressant-like effects of IRN. The antidepressant-like effects of IRN was determined by using animal models of depression including forced swimming and tail suspension tests. The acting mechanism was explored by determining the effect of IRN on the levels of monoamine neurotransmitters and the activities of monoamine oxidases. Intragastric administration of IRN at 10, 20 and 40 mg/kg for 7 days caused a significant reduction of immobility time in both forced swimming and tail suspension tests, while IRN did not stimulate locomotor activity in the open-field test. In addition, IRN treatment antagonized reserpine-induced ptosis and significantly enhanced the levels of monoamine neurotransmitters including norepinephrine (NE) and 5-hydroxytryptamine (5-HT), and the activity of monoamine oxidase A (MAO-A) in the hippocampus and frontal cortex of mice. These results suggest that the antidepressant-like effects of IRN are mediated, at least in part, by the inhibition of monoamine oxidases.


Isorhynchophylline Antidepressant-like effect Forced swimming test Tail suspension test Reserpine antagonism Monoamine neurotransmitter 



This study was partially supported by a Seeding Fund from the School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong (Project Number: 2015.1.081).


  1. 1.
    Kessler RC (2012) The costs of depression. Psychiatr Clin North Am 35:1–14CrossRefPubMedGoogle Scholar
  2. 2.
    Manji HK, Drevets WC, Charney DS (2010) The cellular neurobiology of depression. Nat Med 7:541–547CrossRefGoogle Scholar
  3. 3.
    Covington HE 3rd, Vialou V, Nestler EJ (2010) From synapse to nucleus: novel targets for treating depression. Neuropharmacology 58:683–693CrossRefPubMedGoogle Scholar
  4. 4.
    Laakmann G, Dienel A, KIeser M (1998) Clinical significance of hyperforin for the efficacy of Hypericum extracts on depressive disorders of different severities. Phytomedicine 5:435–442CrossRefPubMedGoogle Scholar
  5. 5.
    Jiang ML, Zhang ZX, Li YZ, Wang XH, Yan W, Gong GQ (2015) Antidepressant-like effect of evodiamine on chronic unpredictable mild stress rats. Neurosci Lett 588:154–158CrossRefPubMedGoogle Scholar
  6. 6.
    Xu Y, Ku BS, Yao HY et al (2005) The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 518:40–46CrossRefPubMedGoogle Scholar
  7. 7.
    Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH et al (2005) Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 82:200–206CrossRefPubMedGoogle Scholar
  8. 8.
    Liu B, Xu C, Wu X, Liu F, Du Y, Sun J et al (2015) Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation. Neuroscience 294:193–205CrossRefPubMedGoogle Scholar
  9. 9.
    Gong MJ, Han B, Wang SM, Liang SW, Zou ZJ (2016) Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats. J Pharm Biomed Anal 123:63–73CrossRefPubMedGoogle Scholar
  10. 10.
    Chen J, Lin D, Zhang C (2015) Antidepressant-like effects of ferulic acid: involvement of serotonergic and norepinergic systems. Metab Brain Dis 30:129–136CrossRefPubMedGoogle Scholar
  11. 11.
    Kang TH, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H et al (2004) Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their action. Life Sci 76:331–343CrossRefPubMedGoogle Scholar
  12. 12.
    Yuan D, Ma B, Yang JY (2009) Anti-inflammatory effects of rhynchophylline and isorhynchophylline in rat N9 microglial cells and the molecular mechanism. Int Immunopharmacol 9:1549–1554CrossRefPubMedGoogle Scholar
  13. 13.
    Shimada Y, Goto H, Itoh T, Sakakibara I, Kubo M, Sasaki H et al (1999) Evaluation of the protective effects of alkaloids isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death in cultured cerebellar granule cells from rats. J Pharm Pharmacol 51:715–722CrossRefPubMedGoogle Scholar
  14. 14.
    Kanatani H, Kohda H, Yamasaki K (1985) The active principle of the branchlets and hook of Uncaria sinensis Oliv. examined with a 5-hydroxytryptamine receptor-binding assay. J Pharm Pharmacol 37:401–404CrossRefPubMedGoogle Scholar
  15. 15.
    Matsumoto K, Morishige R, Murakami Y (2005) Suppressive effects of isorhynchophylline on 5-HT2A receptor function in the brain: behavioural and electrophysiological studies. Eur J Pharmacol 517:191–199CrossRefPubMedGoogle Scholar
  16. 16.
    Lu JH, Tan JQ, Durairajan SS (2012) Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy. Autophagy 8:98–108CrossRefPubMedGoogle Scholar
  17. 17.
    Xian YF, Lin ZX, Mao QQ, Ip SP, Su ZR, Lai XP (2012) Protective effect of isorhynchophylline against β-amyloid-induced neurotoxicity in PC12 cells. Cell Mol Neurobiol 32:353–360CrossRefPubMedGoogle Scholar
  18. 18.
    Xian YF, Lin ZX, Mao QQ, Zhao M, Hu Z, Ip SP (2012) Bioassay-guided isolation of neuroprotective compounds from Uncaria rhynchophylla against beta-amyloid-induced neurotoxicity in PC12 cells. Evid Based Complement Alternat Med 2012:802625PubMedPubMedCentralGoogle Scholar
  19. 19.
    Xian YF, Mao QQ, Wu JC, Su ZR, Chen JN, Lai XP et al (2014) Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. J Alzheimers Dis 39:331–346PubMedGoogle Scholar
  20. 20.
    Huang B, Wu Q, Wen G, Lu Y, Shi J (2001) The distribution of isorhynchophylline in the tissues of the rats and the determination of its plasma half-time. Acta Academiae Medicinae Zunyi 24:119–120Google Scholar
  21. 21.
    Haginiwa J, Sakai S, Aimi N, Yamanaka E, Shinma N (1973) Studies of plants containing indole alkaloids. 2. On the alkaloids of Uncaria rhynchophylla Miq. Yakugaku Zasshi 93:448–452PubMedGoogle Scholar
  22. 22.
    Porsolt RD, Pichon MLE, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressant. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  23. 23.
    Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370CrossRefGoogle Scholar
  24. 24.
    Herrera-Ruiz M, García-Beltrán Y, Mora S (2006) Antidepressant and anxiolytic effects of hydroalcoholic extract from Salvia elegans. J Ethnopharmacol 107:53–58CrossRefPubMedGoogle Scholar
  25. 25.
    Bourin M, Poncelet M, Chermat R, Simon P (1983) The value of the reserpine test in psychopharmacology. Arzneimittelforschung 33:1173–1176PubMedGoogle Scholar
  26. 26.
    Sánchez-Mateo CC, Bonkanka CX, Prado B, Rabanal RM (2007) Antidepressant activity of some Hypericum reflexum L. fil. Extracts in the forced swimming test in mice. J Ethnopharmacol 112:115–121CrossRefPubMedGoogle Scholar
  27. 27.
    Yu ZF, Kong LD, Chen Y (2002) Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol 83:161–165CrossRefPubMedGoogle Scholar
  28. 28.
    Zhou BH, Li XJ, Yang D (2006) Effect of apocynum venetum on the activity of MAO in mice. China Pharmacist 9:689–692Google Scholar
  29. 29.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  30. 30.
    Fuchs E, Fliugge G (2006) Experimental animal models for the simulation of depression and anxiety. Dialogues Clin Neurosci 8:323–333PubMedPubMedCentralGoogle Scholar
  31. 31.
    Yin C, Gou L, Liu Y (2011) Antidepressant-like effects of l-theanine in the forced swim and tail suspension tests in mice. Phytother Res 25:1636–1639CrossRefPubMedGoogle Scholar
  32. 32.
    Bourin M, Fiocco AJ, Clenet F (2001) How valuable are animal models on defining antidepressant activity? Hum Psychopharmacol 16:9–21CrossRefPubMedGoogle Scholar
  33. 33.
    Jans LA, Riedel WJ, Markus CR, Blokland A (2007) Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol Psychiatry 12:522–543CrossRefPubMedGoogle Scholar
  34. 34.
    Savegnago L, Jesse CR, Pinto LG, Rocha JB, Nogueira CW, Zeni G (2007) Monoaminergic agents modulate antidepressant-like effect caused by diphenyl diselenide in rats. Prog Neuropsychopharmacol Biol Psychiatry 31:1261–1269CrossRefPubMedGoogle Scholar
  35. 35.
    Yi LT, Li YC, Pan Y (2008) Antidepressant-like effects of psoralidin isolated from the seeds of Psoralea corylifolia in the forced swimming test in mice. Prog Neuropsychopharmacol Biol Psychiatry 32:510–519CrossRefPubMedGoogle Scholar
  36. 36.
    Dhingra D, Sharma A (2006) Antidepressant-like activity of Glycyrrhiza glabra L. in mouse models of immobility tests. Prog Neuropsychopharmacol Biol Psychiatry 30:449–454CrossRefPubMedGoogle Scholar
  37. 37.
    Bryant SG, Brown CS (1986) Current concepts in clinical therapeutics: major affective disorders. Part 1. Clin Pharm 5:304–318PubMedGoogle Scholar
  38. 38.
    Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285–1297CrossRefPubMedGoogle Scholar
  39. 39.
    Foley P, Gerlach M, Youdim MB, Riederer P (2000) MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders. Parkinsonism Relat Disord 6:25–47CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yan-Fang Xian
    • 1
  • Ding Fan
    • 2
  • Siu-Po Ip
    • 1
  • Qing-Qiu Mao
    • 1
  • Zhi-Xiu Lin
    • 1
  1. 1.School of Chinese Medicine, Faculty of MedicineThe Chinese University of Hong KongHong Kong SARPeople’s Republic of China
  2. 2.Shenzhen Wellsoon Pharmaceutical Company LimitedShenzhenChina

Personalised recommendations