Browse > Article
http://dx.doi.org/10.1016/j.jgr.2021.12.004

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)
Publication Information
Journal of Ginseng Research / v.46, no.5, 2022 , pp. 666-674 More about this Journal
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
14-3-3 ${\zeta}$ protein; 20(S)-Protopanaxadiol; Brain-derived neurotrophic factor (BDNF); cAMP response element-binding protein (CREB); Glycogen synthase kinase $3{\beta}$ (GSK $3{\beta}$);
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 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.
2 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.   DOI
3 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.   DOI
4 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.   DOI
5 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.   DOI
6 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.   DOI
7 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.
8 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.   DOI
9 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.   DOI
10 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.   DOI
11 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.   DOI
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 Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 2015;148:114-31.   DOI
14 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.   DOI
15 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.
16 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.
17 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.   DOI
18 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.   DOI
19 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.   DOI
20 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.   DOI
21 Castren E, Kojima M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol Dis 2017;97(Pt B):119-26.   DOI
22 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.   DOI
23 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.   DOI
24 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.
25 Bjorkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology 2016;102:72-9.   DOI
26 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.
27 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.   DOI
28 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.   DOI
29 Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266(5604):730-2.   DOI
30 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.   DOI
31 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.
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.   DOI
33 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.   DOI
34 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.   DOI
35 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.   DOI
36 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.   DOI
37 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.   DOI
38 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.   DOI
39 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.   DOI
40 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.   DOI
41 Ballone A, Centorrino F, Ottmann C. 14-3-3: a case study in PPI modulation. Molecules 2018;23(6):1386.   DOI
42 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.   DOI
43 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.   DOI
44 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.   DOI
45 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.   DOI
46 Muneer A. Wnt and GSK3 signaling pathways in bipolar disorder: clinical and therapeutic implications. Clin Psychopharmacol Neurosci 2017;15(2):100-14.   DOI
47 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.