Advertisement

Molecular Neurobiology

, Volume 54, Issue 4, pp 2801–2812 | Cite as

Plant Natural Product Puerarin Ameliorates Depressive Behaviors and Chronic Pain in Mice with Spared Nerve Injury (SNI)

  • Jia Zhao
  • Dan Luo
  • Zhaohui Liang
  • Lixing Lao
  • Jianhui Rong
Article

Abstract

Simultaneous relief of the pain from body and brain remains an ongoing challenge. The aim of the present study was to clarify whether plant-derived isoflavone puerarin could ameliorate comorbid depression and pain. We investigated the effects of puerarin on depressive-like behaviors and neuropathic pain in C57BL/6 N mice with spared nerve injury (SNI). After SNI surgery, mice were allowed to recover spontaneously for 7 days and subsequently treated with puerarin, anti-depressant citalopram, and analgesic ibuprofen, alone or in combination, for 8 or 14 days. Forced swim test and tail suspension test were used to assess depressive-like behaviors, whereas von Frey filament test was used to estimate the sensitivity to the mechanical stimulation. Our results suggested that puerarin effectively ameliorated depression and pain in SNI mice although citalopram exhibited anti-depressant activity. In contrast, ibuprofen showed lesser activities against SNI-induced depression and pain. Further mechanistic studies revealed the uniqueness of puerarin as follows: (1) puerarin did not recover SNI-induced depletion of reduced glutathione and loss of superoxide dismutase (SOD), whereas citalopram and ibuprofen showed somewhat antioxidant activities; (2) puerarin markedly promoted the activation of CREB pathway although puerarin and citalopram activated ERK pathway to the same extent; (3) puerarin rapidly and persistently induced brain-derived neurotrophic factor (BDNF) expression whereas citalopram only induced BDNF expression after a prolonged stimulation. Collectively, these results suggest that puerarin may ameliorate the SNI-induced depression and pain via activating ERK, CREB, and BDNF pathways. Puerarin may serve as new lead compound for the development of novel therapeutics for depression and pain comorbidity.

Keywords

Depression Pain Puerarin BDNF Spared nerve injury 

Notes

Acknowledgments

This work was supported by General Research Fund (GRF) (HKU 775812 M) from the Research Grants Council of Hong Kong and the Seed Funding for Basic Research Programme, The University of Hong Kong.

Compliance with Ethical Standard

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. 1.
    Licinio J, Wong ML (1999) The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4:317–327CrossRefPubMedGoogle Scholar
  2. 2.
    Lepine JP, Briley M (2004) The epidemiology of pain in depression. Hum Psychopharmacol 19(Suppl 1):S3–7CrossRefPubMedGoogle Scholar
  3. 3.
    Gerrits MM, van Oppen P, van Marwijk HW, Penninx BW, van der Horst HE (2014) Pain and the onset of depressive and anxiety disorders. Pain 155:53–59CrossRefPubMedGoogle Scholar
  4. 4.
    Hunter AM, Leuchter AF, Cook IA, Abrams M (2010) Brain functional changes (QEEG cordance) and worsening suicidal ideation and mood symptoms during antidepressant treatment. Acta Psychiatr Scand 122:461–469CrossRefPubMedGoogle Scholar
  5. 5.
    Demyttenaere K, Jaspers L (2008) Review: Bupropion and SSRI-induced side effects. J Psychopharmacol 22:792–804CrossRefPubMedGoogle Scholar
  6. 6.
    Munzer A, Sack U, Mergl R, Schonherr J, Petersein C, Bartsch S, Kirkby KC, Bauer K et al (2013) Impact of antidepressants on cytokine production of depressed patients in vitro. Toxins 5:2227–2240CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P (2011) Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 108:9262–9267CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Powell TR, Schalkwyk LC, Heffernan AL, Breen G, Lawrence T, Price T, Farmer AE, Aitchison KJ et al (2013) Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response. Eur Neuropsychopharmacol 23:1105–1114CrossRefPubMedGoogle Scholar
  9. 9.
    Alboni S, Benatti C, Capone G, Corsini D, Caggia F, Tascedda F, Mendlewicz J, Brunello N (2010) Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats. Eur J Pharmacol 643:180–187CrossRefPubMedGoogle Scholar
  10. 10.
    Angst MS, Clark JD, Carvalho B, Tingle M, Schmelz M, Yeomans DC (2008) Cytokine profile in human skin in response to experimental inflammation, noxious stimulation, and administration of a COX-inhibitor: a microdialysis study. Pain 139:15–27CrossRefPubMedGoogle Scholar
  11. 11.
    Endres S, Whitaker RE, Ghorbani R, Meydani SN, Dinarello CA (1996) Oral aspirin and ibuprofen increase cytokine-induced synthesis of IL-1 beta and of tumour necrosis factor-alpha ex vivo. Immunology 87:264–270CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Leuchter AF, Husain MM, Cook IA, Trivedi MH, Wisniewski SR, Gilmer WS, Luther JF, Fava M et al (2010) Painful physical symptoms and treatment outcome in major depressive disorder: a STAR*D (Sequenced Treatment Alternatives to Relieve Depression) report. Psychol Med 40:239–251CrossRefPubMedGoogle Scholar
  13. 13.
    Tao W, Luo X, Cui B, Liang D, Wang C, Duan Y, Li X, Zhou S et al (2015) Practice of traditional Chinese medicine for psycho-behavioral intervention improves quality of life in cancer patients: a systematic review and meta-analysis. Oncotarget 6:39725–39739PubMedPubMedCentralGoogle Scholar
  14. 14.
    Yuan QL, Guo TM, Liu L, Sun F, Zhang YG (2015) Traditional Chinese medicine for neck pain and low back pain: a systematic review and meta-analysis. PLoS ONE 10, e0117146CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Li Q, Yue N, Liu SB, Wang ZF, Mi WL, Jiang JW, Wu GC, Yu J et al (2014) Effects of chronic electroacupuncture on depression- and anxiety-like behaviors in rats with chronic neuropathic pain. Evid Based Complement Alternat Med 2014:158987PubMedPubMedCentralGoogle Scholar
  16. 16.
    Qi H, Han Y, Rong J (2012) Potential roles of PI3K/Akt and Nrf2-Keap1 pathways in regulating hormesis of Z-ligustilide in PC12 cells against oxygen and glucose deprivation. Neuropharmacology 62:1659–1670CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng Y, Yang C, Zhao J, Tse HF, Rong J (2015) Proteomic identification of calcium-binding chaperone calreticulin as a potential mediator for the neuroprotective and neuritogenic activities of fruit-derived glycoside amygdalin. J Nutr Biochem 26:146–154CrossRefPubMedGoogle Scholar
  18. 18.
    Zhao J, Cheng YY, Fan W, Yang CB, Ye SF, Cui W, Wei W, Lao LX et al (2015) Botanical drug puerarin coordinates with nerve growth factor in the regulation of neuronal survival and neuritogenesis via activating ERK1/2 and PI3K/Akt signaling pathways in the neurite extension process. CNS Neurosci Ther 21:61–70CrossRefPubMedGoogle Scholar
  19. 19.
    Mahdy HM, Mohamed MR, Emam MA, Karim AM, Abdel-Naim AB, Khalifa AE (2014) The anti-apoptotic and anti-inflammatory properties of puerarin attenuate 3-nitropropionic-acid induced neurotoxicity in rats. Can J Physiol Pharmacol 92:252–258CrossRefPubMedGoogle Scholar
  20. 20.
    Kim J, Kim KM, Kim CS, Sohn E, Lee YM, Jo K, Kim JS (2012) Puerarin inhibits the retinal pericyte apoptosis induced by advanced glycation end products in vitro and in vivo by inhibiting NADPH oxidase-related oxidative stress. Free Radic Biol Med 53:357–365CrossRefPubMedGoogle Scholar
  21. 21.
    Kim KM, Jung DH, Jang DS, Kim YS, Kim JM, Kim HN, Surh YJ, Kim JS (2010) Puerarin suppresses AGEs-induced inflammation in mouse mesangial cells: a possible pathway through the induction of heme oxygenase-1 expression. Toxicol Appl Pharmacol 244:106–113CrossRefPubMedGoogle Scholar
  22. 22.
    Xu C, Xu W, Xu H, Xiong W, Gao Y, Li G, Liu S, Xie J et al (2012) Role of puerarin in the signalling of neuropathic pain mediated by P2X3 receptor of dorsal root ganglion neurons. Brain Res Bull 87:37–43CrossRefPubMedGoogle Scholar
  23. 23.
    Zhao J, Cheng Y, Yang C, Lau S, Lao L, Shuai B, Cai J, Rong J (2015) Botanical drug puerarin attenuates 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via upregulating mitochondrial enzyme arginase-2. Mol Neurobiol. [Epub ahead of print]Google Scholar
  24. 24.
    Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB (2011) The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J Vis Exp (54):3092. doi: 10.3791/3092
  25. 25.
    Gai BM, Bortolatto CF, Bruning CA, Zborowski VA, Stein AL, Zeni G, Nogueira CW (2014) Depression-related behavior and mechanical allodynia are blocked by 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene in a mouse model of neuropathic pain induced by partial sciatic nerve ligation. Neuropharmacology 79:580–589CrossRefPubMedGoogle Scholar
  26. 26.
    Dimitrov EL, Tsuda MC, Cameron HA, Usdin TB (2014) Anxiety- and depression-like behavior and impaired neurogenesis evoked by peripheral neuropathy persist following resolution of prolonged tactile hypersensitivity. J Neurosci 34:12304–12312CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang J, Goffer Y, Xu D, Tukey DS, Shamir DB, Eberle SE, Zou AH, Blanck TJ et al (2011) A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 115:812–821CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bourquin AF, Suveges M, Pertin M, Gilliard N, Sardy S, Davison AC, Spahn DR, Decosterd I (2006) Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse. Pain 122:14 e11–14CrossRefGoogle Scholar
  29. 29.
    Gureje O (2007) Psychiatric aspects of pain. Curr Opin Psychiatry 20:42–46CrossRefPubMedGoogle Scholar
  30. 30.
    Yasuda S, Yoshida M, Yamagata H, Iwanaga Y, Suenaga H, Ishikawa K, Nakano M, Okuyama S et al (2014) Imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor. Cell Mol Neurobiol 34:1199–1208CrossRefPubMedGoogle Scholar
  31. 31.
    Iyengar RL, Gandhi S, Aneja A, Thorpe K, Razzouk L, Greenberg J, Mosovich S, Farkouh ME (2013) NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med 126:1017 e101–1018CrossRefGoogle Scholar
  32. 32.
    Saleh LA, Hamza M, El Gayar NH, Abd El-Samad AA, Nasr EA, Masoud SI (2014) Ibuprofen suppresses depressive like behavior induced by BCG inoculation in mice: role of nitric oxide and prostaglandin. Pharmacol Biochem Behav 125:29–39CrossRefPubMedGoogle Scholar
  33. 33.
    Caspani O, Reitz MC, Ceci A, Kremer A, Treede RD (2014) Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats. Pharmacol Biochem Behav 124:290–296CrossRefPubMedGoogle Scholar
  34. 34.
    Jaggi AS, Jain V, Singh N (2011) Animal models of neuropathic pain. Fundam Clin Pharmacol 25:1–28CrossRefPubMedGoogle Scholar
  35. 35.
    Numakawa T, Richards M, Nakajima S, Adachi N, Furuta M, Odaka H, Kunugi H (2014) The role of brain-derived neurotrophic factor in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition. Front Psychol 5:136Google Scholar
  36. 36.
    Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci 8:430CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ishikawa K, Yasuda S, Fukuhara K, Iwanaga Y, Ida Y, Ishikawa J, Yamagata H, Ono M et al (2014) 4-Methylcatechol prevents derangements of brain-derived neurotrophic factor and TrkB-related signaling in anterior cingulate cortex in chronic pain with depression-like behavior. Neuroreport 25:226–232CrossRefPubMedGoogle Scholar
  38. 38.
    Pinnock SB, Blake AM, Platt NJ, Herbert J (2010) The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine. PLoS ONE 5, e13652CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW (2008) Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 29:1380–1393CrossRefPubMedGoogle Scholar
  40. 40.
    Liu Y, Lan N, Ren J, Wu Y, Wang ST, Huang XF, Yu Y (2015) Orientin improves depression-like behavior and BDNF in chronic stressed mice. Mol Nutr Food Res 59(6):1130–42Google Scholar
  41. 41.
    Pandey SC, Roy A, Zhang H, Xu T (2004) Partial deletion of the cAMP response element-binding protein gene promotes alcohol-drinking behaviors. J Neurosci 24:5022–5030CrossRefPubMedGoogle Scholar
  42. 42.
    Reinhart V, Bove SE, Volfson D, Lewis DA, Kleiman RJ, Lanz TA (2015) Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder. Neurobiol Dis 77:220–227CrossRefPubMedGoogle Scholar
  43. 43.
    Hashimoto K (2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 64:341–357CrossRefPubMedGoogle Scholar
  44. 44.
    Polyakova M, Stuke K, Schuemberg K, Mueller K, Schoenknecht P, Schroeter ML (2015) BDNF as a biomarker for successful treatment of mood disorders: a systematic & quantitative meta-analysis. J Affect Disord 174:432–440CrossRefPubMedGoogle Scholar
  45. 45.
    Matsuoka Y, Yang J (2012) Selective inhibition of extracellular signal-regulated kinases 1/2 blocks nerve growth factor to brain-derived neurotrophic factor signaling and suppresses the development of and reverses already established pain behavior in rats. Neuroscience 206:224–236CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Jeon SJ, Rhee SY, Seo JE, Bak HR, Lee SH, Ryu JH, Cheong JH, Shin CY et al (2011) Oroxylin A increases BDNF production by activation of MAPK-CREB pathway in rat primary cortical neuronal culture. Neurosci Res 69:214–222CrossRefPubMedGoogle Scholar
  47. 47.
    Wang H, Yuan G, Prabhakar NR, Boswell M, Katz DM (2006) Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling. J Neurochem 96:694–705CrossRefPubMedGoogle Scholar
  48. 48.
    Rosa JM, Dafre AL, Rodrigues AL (2013) Antidepressant-like responses in the forced swimming test elicited by glutathione and redox modulation. Behav Brain Res 253:165–172CrossRefPubMedGoogle Scholar
  49. 49.
    Talarowska M, Szemraj J, Berk M, Maes M, Galecki P (2015) Oxidant/antioxidant imbalance is an inherent feature of depression. BMC Psychiatry 15:71CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mlyniec K, Budziszewska B, Holst B, Ostachowicz B, Nowak G (2015) GPR39 (zinc receptor) knockout mice exhibit depression-like behavior and CREB/BDNF down-regulation in the hippocampus. Int J Neuropsychopharmacol 18(3):1–8Google Scholar
  51. 51.
    Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I (2015) The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 77:236–245CrossRefPubMedGoogle Scholar
  52. 52.
    Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25:1089–1094CrossRefPubMedGoogle Scholar
  53. 53.
    Carreno FR, Frazer A (2014) Activation of signaling pathways downstream of the brain-derived neurotrophic factor receptor, TrkB, in the rat brain by vagal nerve stimulation and antidepressant drugs. Int J Neuropsychopharmacol 17:247–258CrossRefPubMedGoogle Scholar
  54. 54.
    Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA (2002) cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 22:3262–3268PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jia Zhao
    • 1
  • Dan Luo
    • 1
  • Zhaohui Liang
    • 1
  • Lixing Lao
    • 1
  • Jianhui Rong
    • 1
  1. 1.School of Chinese Medicine, Li Ka Shing Faculty of MedicineUniversity of Hong KongPokfulamHong Kong

Personalised recommendations