Advertisement

Psychopharmacology

, Volume 235, Issue 1, pp 233–244 | Cite as

Dihydromyricetin exerts a rapid antidepressant-like effect in association with enhancement of BDNF expression and inhibition of neuroinflammation

  • Zhaoxiang Ren
  • Pengju Yan
  • Liushuai Zhu
  • Huicui Yang
  • Yafei Zhao
  • Brian P. Kirby
  • John L. Waddington
  • Xuechu Zhen
Original Investigation

Abstract

Rationale

Major depressive disorder (MDD) is a highly prevalent illness that affects large populations across the world, and increasing evidence suggests that neuroinflammation and levels of brain-derived neurotrophic factor (BDNF) are closely related to depression. Dihydromyricetin (DHM) is a kind of flavonoid natural product that has been reported to display multiple pharmacological effects, including anti-inflammatory and anti-oxidative properties, and these may contribute to ameliorate MDD.

Objective

This study investigated the effect of DHM on depression-related phenotypes in various experimental animal models.

Methods

The antidepressant-like effect of DHM was validated via depression-related behavioral tests in naïve male C57BL/6 mice, as well as in the acute lipopolysaccharide-induced mouse model of depression. The chronic unpredicted mild stress (CUMS) mouse model of depression was also used to assess the rapid antidepressant-like effect of DHM by tail suspension test (TST), forced swimming test (FST), locomotor activity, and sucrose preference test (SPT). The expression of BDNF and inflammatory factors were determined through Western blotting and enzyme-linked immunosorbent assay, respectively.

Results

DHM reduced immobility time in the TST and FST both in mice and the acute LPS-induced mouse model of depression. Seven days of DHM treatment ameliorated depression-related behaviors induced by CUMS, whereas similar treatment with the typical antidepressant venlafaxine did not. DHM activated the ERK1/2-CREB pathway and increased glycogen synthase kinase-3 beta (GSK-3β) phosphorylation at ser-9, with upregulation of BDNF expression, in both hippocampal tissues and cultured hippocampal cells.

Conclusion

The present data indicate that DHM exerts a more rapid antidepressant-like effect than does a typical antidepressant, in association with enhancement of BDNF expression and inhibition of neuroinflammation.

Keywords

Dihydromyricetin Antidepressant activity Brain-derived neurotrophic factor ERK1/2 Glycogen synthase kinase-3β 

Notes

Acknowledgements

This work was supported by funds from the National Science Foundation of China (81130023, 30825042). Support provided from the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD) and the Jiangsu key laboratory grant (BM2013003) is also appreciated.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

213_2017_4761_MOESM1_ESM.doc (43 kb)
Fig. S1 (DOC 43 kb)

References

  1. Abe-Higuchi N, Uchida S, Yamagata H, Higuchi F, Hobara T, Hara K, Kobayashi A, Watanabe Y (2016) Hippocampal Sirtuin 1 signaling mediates depression-like behavior. Biol Psychiatry 80:815–826CrossRefPubMedGoogle Scholar
  2. Beurel E, Jope RS (2010) Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience 169:1063–1070CrossRefPubMedPubMedCentralGoogle Scholar
  3. BoJiang, LuSong, Cheng-NiuWang, WeiZhang, ChaoHuang, Li-JuanTong (2016) Antidepressant-like effects of GM1 ganglioside involving the BDNF signaling cascade in mice. International Journal of Neuropsychopharmacology 19: pyw046Google Scholar
  4. Bui C, Barter MJ, Scott JL, Xu Y, Galler M, Reynard LN, Rowan AD, Young DA (2012) cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. Faseb Journal Official Publication of the Federation of American Societies for. Exp Biol 26:3000–3011Google Scholar
  5. Chan SY, Matthews E, Burnet PW (2016) ON or OFF?: modulating the N-methyl-D-aspartate receptor in major depression. Front Mol Neurosci 9:169PubMedGoogle Scholar
  6. Chen S, Zhao X, Wan J, Ran L, Qin Y, Wang X, Gao Y, Shu F, Zhang Y, Liu P, Zhang Q, Zhu J, Mi M (2015) Dihydromyricetin improves glucose and lipid metabolism and exerts anti-inflammatory effects in nonalcoholic fatty liver disease: a randomized controlled trial. Pharmacol Res 99:74–81CrossRefPubMedGoogle Scholar
  7. Cheng J, Salton SR (2013) The role of neurotrophins in major depressive disorder. Transl Neurosci 4:46–58Google Scholar
  8. Dale E, Pehrson AL, Jeyarajah T, Li Y, Leiser SC, Smagin G, Olsen CK, Sanchez C (2016) Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. CNS Spectrums 21:143–161CrossRefPubMedGoogle Scholar
  9. Duman RS, Voleti B (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35:47–56CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dwivedi Y (2013) Involvement of brain-derived neurotrophic factor in late-life depression. Am J Geriatr Psychiatr : Off J Am Assoc Geriatr Psychiatr 21:433–449CrossRefGoogle Scholar
  11. Eyre HA, Lavretsky H, Kartika J, Qassim A, Baune BT (2016) Modulatory effects of antidepressant classes on the innate and adaptive immune system in depression. Pharmacopsychiatry 49:85–96CrossRefPubMedPubMedCentralGoogle Scholar
  12. Fang X, Guo L, Jia J, Jin GZ, Zhao B, Zheng YY, Li JQ, Zhang A, Zhen XC (2013) SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity. Acta Pharmacol Sin 34:1149–1155CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gimenez-Cassina A, Lim F, Diaz-Nido J (2012) Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion. Neurosci Lett 531:182–187CrossRefPubMedGoogle Scholar
  14. Guan XT, Lin WJ, Tang MM (2015) Comparison of stress-induced and LPS-induced depressive-like behaviors and the alterations of central proinflammatory cytokines mRNA in rats. PsyCh J 4:113–122CrossRefPubMedGoogle Scholar
  15. Harrisberger F, Smieskova R, Schmidt A, Lenz C, Walter A, Wittfeld K, Grabe HJ, Lang UE, Fusar-Poli P, Borgwardt S (2015) BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev 55:107–118CrossRefPubMedGoogle Scholar
  16. Hou XL, Tong Q, Wang WQ, Shi CY, Xiong W, Chen J, Liu X, Fang JG (2015) Suppression of inflammatory responses by dihydromyricetin, a flavonoid from Ampelopsis grossedentata, via inhibiting the activation of NF-kappaB and MAPK signaling pathways. J Nat Prod 78:1689–1696CrossRefPubMedGoogle Scholar
  17. Hughes MM, Connor TJ, Harkin A (2016) Stress-related immune markers in depression: implications for treatment. Int J NeuropsychopharmacolGoogle Scholar
  18. Jangra A, Sriram CS, Lahkar M (2016) Lipopolysaccharide-induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade. Inflammation 39:1441–1452CrossRefPubMedGoogle Scholar
  19. Jiang B, Le L, Pan H, Hu K, Xu L, Xiao P (2014) Dihydromyricetin ameliorates the oxidative stress response induced by methylglyoxal via the AMPK/GLUT4 signaling pathway in PC12 cells. Brain Res Bull 109:117–126CrossRefPubMedGoogle Scholar
  20. Kao SJ, Lee WJ, Chang JH, Chow JM, Chung CL, Hung WY, Chien MH (2017) Suppression of reactive oxygen species-mediated ERK and JNK activation sensitizes dihydromyricetin-induced mitochondrial apoptosis in human non-small cell lung cancer. Environ Toxicol 32:1426–1438CrossRefPubMedGoogle Scholar
  21. Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues AL, Peluffo H, Kaster MP (2017) NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings. Brain Behav ImmunGoogle Scholar
  22. Kurosawa N, Shimizu K, Seki K (2016) The development of depression-like behavior is consolidated by IL-6-induced activation of locus coeruleus neurons and IL-1beta-induced elevated leptin levels in mice. Psychopharmacology 233:1725–1737CrossRefPubMedGoogle Scholar
  23. Le L, Jiang B, Wan W, Zhai W, Xu L, Hu K, Xiao P (2016) Metabolomics reveals the protective of dihydromyricetin on glucose homeostasis by enhancing insulin sensitivity. Sci Rep 6:36184CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liang J, López-Valdés HE, Martínez-Coria H, Lindemeyer AK, Shen Y, Shao XM, Olsen RW (2014) Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer’s disease. Neurochem Res 39:1171–1181CrossRefPubMedGoogle Scholar
  25. Liu S, Ai Q, Feng K, Li Y, Liu X (2016) The cardioprotective effect of dihydromyricetin prevents ischemia-reperfusion-induced apoptosis in vivo and in vitro via the PI3K/Akt and HIF-1alpha signaling pathways. Apoptosis : An Int J Programmed Cell Death 21:1366–1385CrossRefGoogle Scholar
  26. Mai L, Jope RS, Li X (2002) BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents. J Neurochem 82:75–83CrossRefPubMedGoogle Scholar
  27. Manosso LM, Moretti M, Ribeiro CM, Goncalves FM, Leal RB, Rodrigues AL (2015) Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuro-Psychopharmacol Biol Psychiatry 59:59–67CrossRefGoogle Scholar
  28. Mao Q, Gong X, Zhou C, Tu Z, Zhao L, Wang L, Wang X, Sun L, Xia J, Lian B, Chen J, Mu J, Yang D, Xie P (2017) Up-regulation of SIRT6 in the hippocampus induced rats with depression-like behavior via the block Akt/GSK3beta signaling pathway. Behav Brain Res 323:38–46CrossRefPubMedGoogle Scholar
  29. Ni J, Wang X, Chen S, Liu H, Wang Y, Xu X, Cheng J, Jia J, Zhen X (2015) MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav Immun 49:75–85CrossRefPubMedGoogle Scholar
  30. Nuernberg GL, Aguiar B, Bristot G, Fleck MP, Rocha NS (2016) Brain-derived neurotrophic factor increase during treatment in severe mental illness inpatients. Transl Psychiatry 6:e985CrossRefPubMedPubMedCentralGoogle Scholar
  31. O'Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14:511–522CrossRefPubMedGoogle Scholar
  32. Omata N, Chiu CT, Moya PR, Leng Y, Wang Z, Hunsberger JG, Leeds P, Chuang DM (2011) Lentivirally mediated GSK-3beta silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice. Int J Neuropsychopharmacol 14:711–717CrossRefPubMedGoogle Scholar
  33. Park SE, Lawson M, Dantzer R, Kelley KW, McCusker RH (2011) Insulin-like growth factor-I peptides act centrally to decrease depression-like behavior of mice treated intraperitoneally with lipopolysaccharide. J Neuroinflammation 8:179CrossRefPubMedPubMedCentralGoogle Scholar
  34. Pesarico AP, Sartori G, Bruning CA, Mantovani AC, Duarte T, Zeni G, Nogueira CW (2016) A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice. Behav Brain Res 307:73–83CrossRefPubMedGoogle Scholar
  35. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D (2015) Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry 21:71CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ren ZX, Zhao YF, Cao T, Zhen XC (2016) Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson’s disease by suppressing glycogen synthase kinase-3 beta activity. Acta Pharmacol Sin 37:1315–1324CrossRefPubMedPubMedCentralGoogle Scholar
  37. Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Rd YJ, Takemori H (2004) The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119:61CrossRefPubMedGoogle Scholar
  38. Shen Y, Lindemeyer AK, Gonzalez C, Shao XM, Spigelman I, Olsen RW, Liang J (2012) Dihydromyricetin as a novel anti-alcohol intoxication medication. J Neurosci: Off J Soc Neurosci 32:390–401CrossRefGoogle Scholar
  39. Sulakhiya K, Keshavlal GP, Bezbaruah BB, Dwivedi S, Gurjar SS, Munde N, Jangra A, Lahkar M, Gogoi R (2016) Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin. Neurosci Lett 611:106–111CrossRefPubMedGoogle Scholar
  40. Sun J, Wang F, Hong G, Pang M, Xu H, Li H, Tian F, Fang R, Yao Y, Liu J (2016) Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress. Neurosci Lett 618:159–166CrossRefPubMedGoogle Scholar
  41. Tang N, Ma J, Wang KS, Mi C, Lv Y, Piao LX, GH X, Li X, Lee JJ, Jin X (2016) Dihydromyricetin suppresses TNF-alpha-induced NF-kappaB activation and target gene expression. Mol Cell Biochem 422:11–20CrossRefPubMedGoogle Scholar
  42. Tao W, Dong Y, Su Q, Wang H, Chen Y, Xue W, Chen C, Xia B, Duan J, Chen G (2016) Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway. Behav Brain Res 308:177–186CrossRefPubMedGoogle Scholar
  43. Tong Q, Hou X, Fang J, Wang W, Xiong W, Liu X, Xie X, Shi C (2015) Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. J Pharm Biomed Anal 114:455–461CrossRefPubMedGoogle Scholar
  44. Tsai SJ, Liou YJ, Hong CJ, YW Y, Chen TJ (2008) Glycogen synthase kinase-3beta gene is associated with antidepressant treatment response in Chinese major depressive disorder. The Pharmacogenomics J 8:384–390CrossRefPubMedGoogle Scholar
  45. Vogelzangs N, Beekman AT, van Reedt Dortland AK, Schoevers RA, Giltay EJ, de Jonge P, Penninx BW (2014) Inflammatory and metabolic dysregulation and the 2-year course of depressive disorders in antidepressant users. Neuropsychopharmacol : Off Publ Am Coll Neuropsychopharmacol 39:1624–1634CrossRefGoogle Scholar
  46. Wang Y, Guo L, Jiang HF, Zheng LT, Zhang A, Zhen XC (2016) Allosteric modulation of sigma-1 receptors elicits rapid antidepressant activity. CNS Neurosci Ther 22:368–377CrossRefPubMedGoogle Scholar
  47. Wang Y, Lawson MA, Dantzer R, Kelley KW (2010) LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia. Brain Behav Immun 24:201–209CrossRefPubMedGoogle Scholar
  48. Wohleb ES (2016) Neuron-microglia interactions in mental health disorders: “for better, and for worse”. Front Immunol 7:544CrossRefPubMedPubMedCentralGoogle Scholar
  49. Wu Z, Li L, Zheng LT, Xu Z, Guo L, Zhen X (2015) Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. J Neurochem 134:904–914CrossRefPubMedGoogle Scholar
  50. Xie J, Liu J, Chen TM, Lan Q, Zhang QY, Liu B, Dai D, Zhang WD, LP H, Zhu RZ (2015) Dihydromyricetin alleviates carbon tetrachloride-induced acute liver injury via JNK-dependent mechanism in mice. World J Gastroenterol 21:5473–5481CrossRefPubMedPubMedCentralGoogle Scholar
  51. Xu LZ, Xu DF, Han Y, Liu LJ, Sun CY, Deng JH, Zhang RX, Yuan M, Zhang SZ, Li ZM, Xu Y, Li JS, Xie SH, Li SX, Zhang HY, Lu L (2016) BDNF-GSK-3beta-beta-catenin pathway in the mPFC is involved in antidepressant-like effects of Morinda officinalis oligosaccharides in rats. Int J NeuropsychopharmacolGoogle Scholar
  52. Xue W, Wang W, Gong T, Zhang H, Tao W, Xue L, Sun Y, Wang F, Chen G (2016) PKA-CREB-BDNF signaling regulated long lasting antidepressant activities of Yueju but not ketamine. Sci Rep 6:26331CrossRefPubMedPubMedCentralGoogle Scholar
  53. Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (2016) Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. Psychopharmacology 233:3647–3657CrossRefPubMedPubMedCentralGoogle Scholar
  54. Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C (2003) Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 85:180CrossRefPubMedGoogle Scholar
  55. Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, Li SX, Shirayama Y, Hashimoto K (2014) Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. Int J Neuropsychopharmacol 18Google Scholar
  56. Zhao Y, Wang P, Chen S, Han C, Yan Q, Zheng L, Jia J, Ren Z, Zhen X (2017) Dihydromyricetin protects against cerebral ischemia/reperfusion injury via suppressing microglia-mediated neuroinflammation and activation of ERK1/2-CREB signaling pathway. J Funct Foods 33:76–84CrossRefGoogle Scholar
  57. Zhu L, Nang C, Luo F, Pan H, Zhang K, Liu J, Zhou R, Gao J, Chang X, He H, Qiu Y, Wang J, Long H, Liu Y, Yan T (2016) Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice. Physiol Behav 163:184–192CrossRefPubMedGoogle Scholar
  58. Zunszain PA, Horowitz MA, Cattaneo A, Lupi MM, Pariante CM (2013) Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol Psychiatry 18:1236–1241CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Zhaoxiang Ren
    • 1
  • Pengju Yan
    • 1
  • Liushuai Zhu
    • 1
  • Huicui Yang
    • 1
  • Yafei Zhao
    • 1
  • Brian P. Kirby
    • 3
  • John L. Waddington
    • 1
    • 4
  • Xuechu Zhen
    • 1
    • 2
  1. 1.Jiangsu Key laboratory for Translational Research and Therapy for Neuropsychiatric disorders, College of Pharmaceutical SciencesSoochow UniversitySuzhouChina
  2. 2.The Collaborative Innovation Center for Brain ScienceSoochow UniversitySuzhouChina
  3. 3.School of PharmacyRoyal College of Surgeons in IrelandDublin 2Ireland
  4. 4.Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublin 2Ireland

Personalised recommendations