Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

A possible mechanism to the antidepressant-like effects of 20 (S)-protopanaxadiol based on its target protein 14-3-3 ζ

  • Chen, Lin (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Li, Ruimei (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Chen, Feiyan (Research and Innovation Center, College of Traditional Chinese Medicine Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine) ;
  • Zhang, Hantao (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Zhu, Zhu (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Xu, Shuyi (Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Cheng, Yao (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine) ;
  • Zhao, Yunan (Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine)
  • Received : 2021.07.01
  • Accepted : 2021.12.14
  • Published : 2022.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ginsenosides and their metabolites have antidepressant-like effects, but the underlying mechanisms remain unclear. We previously identified 14-3-3 ζ as one of the target proteins of 20 (S)-protopanaxadiol (PPD), a fully deglycosylated ginsenoside metabolite. Methods: Corticosterone (CORT) was administered repeatedly to induce the depression model, and PPD was given concurrently. The tail suspension test (TST) and the forced swimming test (FST) were used for behavioral evaluation. All mice were sacrificed. Golgi-cox staining, GSK 3β activity assay, and Western blot analysis were performed. In vitro, the kinetic binding analysis with the Biolayer Interferometry (BLI) was used to determine the molecular interactions. Results: TST and FST both revealed that PPD reversed CORT-induced behavioral deficits. PPD also ameliorated the CORT-induced expression alterations of hippocampal Ser9 phosphorylated glycogen synthase kinase 3β (p-Ser9 GSK 3β), Ser133 phosphorylated cAMP response element-binding protein (p-Ser133 CREB), and brain-derived neurotrophic factor (BDNF). Moreover, PPD attenuated the CORT-induced increase in GSK 3β activity and decrease in dendritic spine density in the hippocampus. In vitro, 14-3-3 ζ protein specifically bound to p-Ser9 GSK 3β polypeptide. PPD promoted the binding and subsequently decreased GSK 3β activity. Conclusion: These findings demonstrated the antidepressant-like effects of PPD on the CORT-induced mouse depression model and indicated a possible target-based mechanism. The combination of PPD with the 14-3-3 ζ protein may promote the binding of 14-3-3 ζ to p-GSK 3β (Ser9) and enhance the inhibition of Ser9 phosphorylation on GSK 3β kinase activity, thereby activating the plasticity-related CREBeBDNF signaling pathway.

Keywords

Acknowledgement

The study was financially supported by National Natural Science Foundation of China (Nos. 81703732, 81873025, and 82003937), Natural Science Foundation of Jiangsu Provincial (BK20181423), Natural Science Foundation of Colleges and Universities in Jiangsu Province (20KJB360009), and the Natural Science Foundation of Nanjing University of Chinese Medicine (81703732).

References

  1. Jin C, Wang ZZ, Zhou H, Lou YX, Chen J, Zuo W, Tian MT, Wang ZQ, Du GH, Kawahata I, et al. Ginsenoside Rg1-induced antidepressant effects involve the protection of astrocyte gap junctions within the prefrontal cortex. Prog Neuro-Psychopharmacol Biol Psychiatry 2017;75:183-91. https://doi.org/10.1016/j.pnpbp.2016.09.006
  2. Song W, Guo Y, Jiang S, Wei L, Liu Z, Wang X, Su Y. Antidepressant effects of the ginsenoside metabolite compound K, assessed by behavioral despair test and chronic unpredictable mild stress model. Neurochem Res 2018;43(7): 1371-82. https://doi.org/10.1007/s11064-018-2552-5
  3. Zheng M, Xin Y, Li Y, Xu F, Xi X, Guo H, Cui X, Cao H, Zhang X, Han C. Ginsenosides: a potential neuroprotective agent. BioMed Res Int 2018;2018: 8174345.
  4. Jiang N, Lv J, Wang H, Wang Q, Liu X. Antidepressant-like effects of 20(S)- protopanaxadiol in a mouse model of chronic social defeat stress and the related mechanisms. Phytother Res 2019;33(10):2726-36. https://doi.org/10.1002/ptr.6446
  5. Jiang N, Jingwei L, Wang H, Huang H, Wang Q, Zeng G, Li S, Liu X. Ginsenoside 20(S)-protopanaxadiol attenuates depressive-like behaviour and neuroinflammation in chronic unpredictable mild stress-induced depressive rats. Behav Brain Res 2020;393:112710. https://doi.org/10.1016/j.bbr.2020.112710
  6. Chen L, Dai J, Wang Z, Zhang H, Huang Y, Zhao Y. Ginseng total saponins reverse corticosterone-induced changes in depression-like behavior and hippocampal plasticity-related proteins by interfering with GSK-3b-CREB signaling pathway. Evid Based Complement Alternat Med 2014;2014:506735.
  7. Yu H, Fan C, Yang L, Yu S, Song Q, Wang P, Mao X. Ginsenoside Rg1 prevents chronic stress-induced depression-like behaviors and neuronal structural plasticity in rats. Cell Physiol Biochem 2018;48(6):2470-82. https://doi.org/10.1159/000492684
  8. Zhao L, Guo R, Cao N, Lin Y, Yang W, Pei S, Ma X, Zhang Y, Li Y, Song Z, et al. An integrative pharmacology-based pattern to uncover the pharmacological mechanism of ginsenoside H dripping pills in the treatment of depression. Front Pharmacol 2021;11:590457. https://doi.org/10.3389/fphar.2020.590457
  9. Xue W, Liu Y, Qi WY, Gao Y, Li M, Shi AX, Li KX. Pharmacokinetics of ginsenoside Rg1 in rat medial prefrontal cortex, hippocampus, and lateral ventricle after subcutaneous administration. J Asian Nat Prod Res 2016;18(6):587-95. https://doi.org/10.1080/10286020.2016.1177026
  10. Musende AG, Eberding A, Wood CA, Adomat H, Fazli L, Hurtado-Coll A, Jia W, Bally MB, Tomlinson Guns ES. A novel oral dosage formulation of the ginsenoside aglycone protopanaxadiol exhibits therapeutic activity against a hormone-insensitive model of prostate cancer. Anti Cancer Drugs 2012;23(5): 543-52. https://doi.org/10.1097/CAD.0b013e32835006f5
  11. Chen C, Wang L, Cao F, Miao X, Chen T, Chang Q, Zheng Y. Formulation of 20(S)-protopanaxadiol nanocrystals to improve oral bioavailability and brain delivery. Int J Pharm 2016;497(1-2):239-47. https://doi.org/10.1016/j.ijpharm.2015.12.014
  12. Zhao YN, Shao X, Ouyang LF, Chen L, Gu L. Qualitative detection of ginsenosides in brain tissues after oral administration of high-purity ginseng total saponins by using polyclonal antibody against ginsenosides. Chin J Nat Med 2018;16(3):175-83.
  13. Chen F, Chen L, Liang W, Zhang Z, Li J, Zheng W, Zhu Z, Zhu J, Zhao Y. Identification and confirmation of 14-3-3 ζ as a novel target of ginsenosides in brain tissues. J Ginseng Res 2021;45(4):465-72. https://doi.org/10.1016/j.jgr.2020.12.007
  14. Ballone A, Centorrino F, Ottmann C. 14-3-3: a case study in PPI modulation. Molecules 2018;23(6):1386. https://doi.org/10.3390/molecules23061386
  15. Hartman AM, Hirsch AKH. Molecular insight into specific 14-3-3 modulators: inhibitors and stabilisers of protein-protein interactions of 14-3-3. Eur J Med Chem 2017;136:573-84. https://doi.org/10.1016/j.ejmech.2017.04.058
  16. Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 2015;148:114-31. https://doi.org/10.1016/j.pharmthera.2014.11.016
  17. Krishnankutty A, Kimura T, Saito T, Aoyagi K, Asada A, Takahashi SI, Ando K, Ohara-Imaizumi M, Ishiguro K, Hisanaga SI. In vivo regulation of glycogen synthase kinase 3b activity in neurons and brains. Sci Rep 2017;7(1):8602. https://doi.org/10.1038/s41598-017-09239-5
  18. Bradley CA, Peineau S, Taghibiglou C, Nicolas CS, Whitcomb DJ, Bortolotto ZA, Kaang BK, Cho K, Wang YT, Collingridge GL. A pivotal role of GSK-3 in synaptic plasticity. Front Mol Neurosci 2012;5:13.
  19. Dandekar MP, Valvassori SS, Dal-Pont GC, Quevedo J. Glycogen synthase kinase-3 beta as a putative therapeutic target for bipolar disorder. Curr Drug Metabol 2018;19(8):663-73. https://doi.org/10.2174/1389200219666171227203737
  20. Muneer A. Wnt and GSK3 signaling pathways in bipolar disorder: clinical and therapeutic implications. Clin Psychopharmacol Neurosci 2017;15(2):100-14. https://doi.org/10.9758/cpn.2017.15.2.100
  21. Pardo M, Abrial E, Jope RS, Beurel E. GSK3b isoform-selective regulation of depression, memory and hippocampal cell proliferation. Gene Brain Behav 2016;15(3):348-55. https://doi.org/10.1111/gbb.12283
  22. Khan I, Tantray MA, Hamid H, Alam MS, Kalam A, Shaikh F, Shah A, Hussain F. Synthesis of novel pyrimidin-4-one bearing piperazine ring-based amides as glycogen synthase kinase-3b inhibitors with antidepressant activity. Chem Biol Drug Des 2016;87(5):764-72. https://doi.org/10.1111/cbdd.12710
  23. Yang T, Nie Z, Shu H, Kuang Y, Chen X, Cheng J, Yu S, Liu H. The role of BDNF on neural plasticity in depression. Front Cell Neurosci 2020;14:82.
  24. Van Calker D, Serchov T, Normann C, Biber K. Recent insights into antidepressant therapy: distinct pathways and potential common mechanisms in the treatment of depressive syndromes. Neurosci Biobehav Rev 2018;88: 63-72. https://doi.org/10.1016/j.neubiorev.2018.03.014
  25. Castren E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis 2017;97(Pt B):119-26. https://doi.org/10.1016/j.nbd.2016.07.010
  26. Tullai JW, Chen J, Schaffer ME, Kamenetsky E, Kasif S, Cooper GM. Glycogen synthase kinase-3 represses cyclic AMP response element-binding protein (CREB)-targeted immediate early genes in quiescent cells. J Biol Chem 2007;282(13):9482-91. https://doi.org/10.1074/jbc.M700067200
  27. Goni-Oliver P, Avila J, Hernandez F. Calpain regulates N-terminal interaction of GSK-3b with 14-3-3ζ, p53 and PKB but not with axin. Neurochem Int 2011;59(2):97-100. https://doi.org/10.1016/j.neuint.2011.03.021
  28. Chang TC, Liu CC, Hsing EW, Liang SM, Chi YH, Sung LY, Lin SP, Shen TL, Ko BS, Yen BL, et al. 14-3-3 σ regulates β-catenin-mediated mouse embryonic stem cell proliferation by sequestering GSK-3β. PLoS One 2012;7(6):e40193.
  29. Abdiche Y, Malashock D, Pinkerton A, Pons J. Determining kinetics and affinities of protein interactions using a parallel real-time label-free biosensor, the Octet. Anal Biochem 2008;377(2):209-17. https://doi.org/10.1016/j.ab.2008.03.035
  30. Zhao YN, Shao X, Ouyang LF, Chen L, Gu L. Qualitative detection of ginsenosides in brain tissues after oral administration of high-purity ginseng total saponins by using polyclonal antibody against ginsenosides. Chin J Nat Med 2018;16(3):175-83.
  31. Wang YS, Lin Y, Li H, Li Y, Song Z, Jin YH. The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity. Sci Rep 2017;7(1):12408. https://doi.org/10.1038/s41598-017-12572-4
  32. Zhao YN, Ma R, Shen J, Su H, Xing D, Du L. A mouse model of depression induced by repeated corticosterone injections. Eur J Pharmacol 2008;581(1-2):113-20. https://doi.org/10.1016/j.ejphar.2007.12.005
  33. Sousa N, Almeida OF, Holsboer F, Paula-Barbosa MM, Madeira MD. Maintenance of hippocampal cell numbers in young and aged rats submitted to chronic unpredictable stress. Comparison with the effects of corticosterone treatment. Stress 1998;2(4):237-49. https://doi.org/10.3109/10253899809167288
  34. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266(5604):730-2. https://doi.org/10.1038/266730a0
  35. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 1985;85(3):367-70. https://doi.org/10.1007/BF00428203
  36. Duman RS, Deyama S, Fogaca MV. Role of BDNF in the pathophysiology and treatment of depression: activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci 2021;53(1):126-39. https://doi.org/10.1111/ejn.14630
  37. Bjorkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology 2016;102:72-9. https://doi.org/10.1016/j.neuropharm.2015.10.034
  38. Iijima M, Ito A, Kurosu S, Chaki S. Pharmacological characterization of repeated corticosterone injection-induced depression model in rats. Brain Res 2010;1359:75-80. https://doi.org/10.1016/j.brainres.2010.08.078
  39. Huang Q, Wu HL, Cai MX, Xia ZJ, Shang J. Comparison between two animal models of depression induced by corticosterone repeated injection and chronic unpredictable mild stress. Acta Anat Sin 2017;48(3):273-81.
  40. Chaves RC, Mallmann ASV, Oliveira NF, Oliveira ICM, Capibaribe VCC, da Silva DMA, Lopes IS, Valentim JT, de Carvalho AMR, Macedo DS, et al. Reversal effect of Riparin IV in depression and anxiety caused by corticosterone chronic administration in mice. Pharmacol Biochem Behav 2019;180:44-51. https://doi.org/10.1016/j.pbb.2019.03.005
  41. Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY. The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. Neuroscience 2016;322:358-69. https://doi.org/10.1016/j.neuroscience.2016.02.050
  42. Zhang H, Zhou Z, Chen Z, Zhong Z, Li Z. Ginsenoside Rg3 exerts antidepressive effect on an NMDA-treated cell model and a chronic mild stress animal model. J Pharmacol Sci 2017;134(1):45-54. https://doi.org/10.1016/j.jphs.2017.03.007
  43. Lucci C, Mesquita-Ribeiro R, Rathbone A, Dajas-Bailador F. Spatiotemporal regulation of GSK3b levels by miRNA-26a controls axon development in cortical neurons. Development 2020;147(3):dev180232.
  44. Lin K, Liu B, Lim SL, Fu X, Sze SC, Yung KK, Zhang S. 20(S)-protopanaxadiol promotes the migration, proliferation, and differentiation of neural stem cells by targeting GSK-3b in the Wnt/GSK-3β/β-catenin pathway. J Ginseng Res 2020;44(3):475-82. https://doi.org/10.1016/j.jgr.2019.03.001
  45. Zhao H, Liang B, Yu L, Xu Y. Anti-depressant-like effects of Jieyu chufan capsules in a mouse model of unpredictable chronic mild stress. Exp Ther Med 2017;14(2):1086-94. https://doi.org/10.3892/etm.2017.4601
  46. Jensen J, Brennesvik EO, Lai YC, Shepherd PR. GSK-3beta regulation in skeletal muscles by adrenaline and insulin: evidence that PKA and PKB regulate different pools of GSK-3. Cell Signal 2007;19(1):204-10. https://doi.org/10.1016/j.cellsig.2006.06.006
  47. Mwangi S, Anitha M, Fu H, Sitaraman SV, Srinivasan S. Glial cell line-derived neurotrophic factor-mediated enteric neuronal survival involves glycogen synthase kinase-3beta phosphorylation and coupling with 14-3-3. Neuroscience 2006;143(1):241-51. https://doi.org/10.1016/j.neuroscience.2006.07.050