DOI QR코드

DOI QR Code

Antidepressant effects of ginsenoside Rf on behavioral change in the glial degeneration model of depression by reversing glial loss

  • Kim, Yunna (College of Korean Medicine, Kyung Hee University) ;
  • Lee, Hwa-Young (College of Korean Medicine, Kyung Hee University) ;
  • Choi, Yu-Jin (College of Korean Medicine, Kyung Hee University) ;
  • Cho, Seung-Hun (College of Korean Medicine, Kyung Hee University)
  • Received : 2018.09.08
  • Accepted : 2019.08.16
  • Published : 2020.07.15

Abstract

Background: Depression is a common neuropsychiatric disease that shows astrocyte pathology. Ginsenoside Rf (G-Rf) is a saponin found in Panax ginseng which has been used to treat neuropsychiatric diseases. We aimed to investigate antidepressant properties of G-Rf when introduced into the L-alphaaminoadipic acid (L-AAA)-infused mice model which is representative of a major depressive disorder that features diminished astrocytes in the brain. Methods: L-AAA was infused into the prefrontal cortex (PFC) of mice to induce decrease of astrocytes. Mice were orally administered G-Rf (20 mg/kg) as well as vehicle only or imipramine (20 mg/kg) as controls. Depression-like behavior of mice was evaluated using forced swimming test (FST) and tail suspension test (TST). We observed recovery of astroglial impairment and increased proliferative cells in the PFC and its accompanied change in the hippocampus by Western blot and immunohistochemistry to assess the effect of G-Rf. Results: After injection of L-AAA into the PFC, mice showed increased immobility time in FST and TST and loss of astrocytes without significant neuronal change in the PFC. G-Rf-treated mice displayed significantly more decreased immobility time in FST and TST than did vehicle-treated mice, and their immobility time almost recovered to those of the sham mice and imipramine-treated mice. G-Rf upregulated glial fibrillary acidic protein (GFAP) expression and Ki-67 expression in the PFC reduced by L-AAA and also alleviated astroglial change in the hippocampus. Conclusion: G-Rf markedly reversed depression-like behavioral changes and exhibited protective effect against the astrocyte ablation in the PFC induced by L-AAA. These protective properties suggest that G-Rf might be a therapeutic agent for major depressive disorders.

Keywords

References

  1. Rial D, Lemos C, Pinheiro H, Duarte JM, Goncalves FQ, Real JI, Prediger RD, Goncalves N, Gomes CA, Canas PM, et al. Depression as a glial-based synaptic dysfunction. Front Cell Neurosci 2015;9:521.
  2. Lee S, Jeong J, Kwak Y, Park SK. Depression research: where are we now? Mol Brain 2010;3:8. https://doi.org/10.1186/1756-6606-3-8
  3. Rajkowska G, Stockmeier C A. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 2013;14:1225-36. https://doi.org/10.2174/13894501113149990156
  4. Miguel-Hidalgo JJ, Baucom C, Dilley G, Overholser JC, Meltzer HY, Stockmeier CA, Rajkowska G. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol Psychiatry 2000;48:861-73. https://doi.org/10.1016/S0006-3223(00)00999-9
  5. Wang Q, Jie W, Liu JH, Yang JM, Gao TM. An astroglial basis of major depressive disorder? An overview. Glia 2017;65:1227-50. https://doi.org/10.1002/glia.23143
  6. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proceed Natl Acad Sci 1998;95:13290-5. https://doi.org/10.1073/pnas.95.22.13290
  7. Cobb JA, O'Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL, Miguel-Hidalgo J, Rajkowska G, Stockmeier CA. Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience 2016;316:209-20. https://doi.org/10.1016/j.neuroscience.2015.12.044
  8. Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005;6:626. https://doi.org/10.1038/nrn1722
  9. Domin H, Szewczyk B, Pochwat B, Wozniak M, Smialowska M. Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810:behavioral, molecular, and immunohistochemical evidence. Psychopharmacology (Berl) 2017;234:631-45. https://doi.org/10.1007/s00213-016-4495-3
  10. Takada M, Hattori T. Fine structural changes in the rat brain after local injections of gliotoxin, alpha-aminoadipic acid. Histol Histopathol 1986;1:271-5.
  11. Banasr M, Duman RS. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 2008;64:863-70. https://doi.org/10.1016/j.biopsych.2008.06.008
  12. Lee Y, Son H, Kim G, Kim S, Lee DH, Roh GS, Kang SS, Cho GJ, Choi WS, Kim HJ. Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice. J Psychiatr Neurosci JPN 2013;38:183-91. https://doi.org/10.1503/jpn.120024
  13. Dang H, Chen Y, Liu X, Wang Q, Wang L, Jia W, Wang Y. Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression. Prog Neuropsychopharmacol Biol Psychiatr 2009;33:1417-24. https://doi.org/10.1016/j.pnpbp.2009.07.020
  14. Choi JH, Lee MJ, Jang M, Kim H-J, Lee S, Lee SW, et al. Panax ginseng exerts antidepressant-like effects by suppressing neuroinflammatory response and upregulating nuclear factor erythroid 2 related factor 2 signaling in the amygdala. J Ginseng Res 2018 Jan;42(1):107-15. https://doi.org/10.1016/j.jgr.2017.04.012. Epub 2017 Apr 29.
  15. Yamada N, Araki H, Yoshimura H. Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors. Psychopharmacology (Berl) 2011;216:589-99. https://doi.org/10.1007/s00213-011-2252-1
  16. Lee B, Kim H, Shim I, Lee H, Hahm D-H. Wild ginseng attenuates anxiety-and depression-like behaviors during morphine withdrawal. J Microbiol Biotechnol 2011;21:1088-96. https://doi.org/10.4014/jmb.1106.06027
  17. Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu S. 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
  18. Zheng X, Liang Y, Kang A, Ma S-J, Xing L, Zhou Y-Y, Dai C, Xie H, Xie L, Wang GJ. Peripheral immunomodulation with ginsenoside Rg1 ameliorates neuroinflammation-induced behavioral deficits in rats. Neuroscience 2014;256:210-22. https://doi.org/10.1016/j.neuroscience.2013.10.023
  19. Cui J, Jiang L, Xiang H. Ginsenoside Rb3 exerts antidepressant-like effects in several animal models. J Psychopharmacol 2012;26:697-713. https://doi.org/10.1177/0269881111415735
  20. Xu C, Teng J, Chen W, Ge Q, Yang Z, Yu C, Yang Z, Jia W. 20 (S)-protopanaxadiol, an active ginseng metabolite, exhibits strong antidepressant-like effects in animal tests. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1402-11. https://doi.org/10.1016/j.pnpbp.2010.07.010
  21. Mogil JS, Shin Y-H, McCleskey EW, Kim S-C, Nah S-Y. Ginsenoside Rf, a trace component of ginseng root, produces antinociception in mice. Brain Res 1998;792:218-28. https://doi.org/10.1016/S0006-8993(98)00133-4
  22. Nemmani KV, Ramarao P. Ginsenoside Rf potentiates U-50,488 H-induced analgesia and inhibits tolerance to its analgesia in mice. Life Sci 2003;72:759-68. https://doi.org/10.1016/S0024-3205(02)02333-0
  23. Kim MK, Kang H, Baek CW, Jung YH, Woo YC, Choi GJ, et al. Antinociceptive and anti-inflammatory effects of ginsenoside Rf in a rat model of incisional pain. Journal of Ginseng Res 2018 Apr;42(2):183-91. https://doi.org/10.1016/j.jgr.2017.02.005. Epub 2017 Mar 2.
  24. Bae E-A, Han MJ, Shin Y-W, Kim D-H. Inhibitory effects of Korean red ginseng and its genuine constituents ginsenosides Rg3, Rf, and Rh2 in mouse passive cutaneous anaphylaxis reaction and contact dermatitis models. Biol Pharm Bull 2006;29:1862-7. https://doi.org/10.1248/bpb.29.1862
  25. Huang P, Tunis J, Parry C, Tallarida R, Liu-Chen LY. Synergistic antidepressantlike effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test. Eur J Pharmacol 2016;781:53-9. https://doi.org/10.1016/j.ejphar.2016.03.061
  26. Mineur YS, Belzung C, Crusio WE. Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice. Behav Brain Res 2006;175:43-50. https://doi.org/10.1016/j.bbr.2006.07.029
  27. David J, Gormley S, McIntosh A, Kebede V, Thuery G, Varidaki A, Coffey E, Harkin A. L-alpha-amino adipic acid provokes depression-like behaviour and a stress related increase in dendritic spine density in the pre-limbic cortex and hippocampus in rodents. Behav Brain Res 2019;362:90-102. https://doi.org/10.1016/j.bbr.2019.01.015
  28. Domin H, Szewczyk B, Wozniak M, Wawrzak-Wlecial A, Smialowska M. Antidepressant-like effect of the mGluR5 antagonist MTEP in an astroglial degeneration model of depression. Behav Brain Res 2014;273:23-33. https://doi.org/10.1016/j.bbr.2014.07.019
  29. Haghparast A, Taslimi Z, Ramin M, Azizi P, Khodagholi F, Hassanpour-Ezatti M. Changes in phosphorylation of CREB, ERK, and c-fos induction in rat ventral tegmental area, hippocampus and prefrontal cortex after conditioned place preference induced by chemical stimulation of lateral hypothalamus. Behav Brain Res 2011;220:112-8. https://doi.org/10.1016/j.bbr.2011.01.045
  30. Shirayama Y, Takahashi M, Osone F, Hara A, Okubo T. Myo-inositol, glutamate, and glutamine in the prefrontal cortex, Hippocampus, and amygdala in major depression. Biol Psychiatr Cogn Neurosci Neuroimaging 2017;2:196-204.
  31. Slattery DA, Cryan JF. The ups and downs of modelling mood disorders in rodents. ILAR J 2014;55:297-309. https://doi.org/10.1093/ilar/ilu026
  32. Goodwin GM. Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression: 20 years on. J Psychopharmacol 2016;30:1090-4. https://doi.org/10.1177/0269881116661074
  33. Czeh B, Fuchs E, Wiborg O, Simon M. Animal models of major depression and their clinical implications. Prog Neuropsychopharmacol Biol Psychiatry 2016;64:293-310. https://doi.org/10.1016/j.pnpbp.2015.04.004
  34. Arnone D, Mumuni AN, Jauhar S, Condon B, Cavanagh J. Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: meta-analysis of absolute prefrontal neuro-metabolic concentrations. Eur Neuropsychopharmacol 2015;25:1109-17. https://doi.org/10.1016/j.euroneuro.2015.04.016
  35. Etievant A, Oosterhof C, Betry C, Abrial E, Novo-Perez M, Rovera R, Scarna H, Devader C, Mazella J, Wegener G, et al. Astroglial control of the antidepressant-like effects of prefrontal cortex deep brain stimulation. EBio-Medicine 2015;2:898-908.
  36. Vertes RP. Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat. Neuroscience 2006;142:1-20. https://doi.org/10.1016/j.neuroscience.2006.06.027
  37. Sigurdsson T, Duvarci S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Front Syst Neurosci 2016;9.
  38. Jin J, Maren S. Prefrontal-hippocampal interactions in memory and emotion. Front Syst Neurosci 2015;9.
  39. Kim H. Neuroprotective herbs for stroke therapy in traditional eastern medicine. Neurol Res 2005;27:287-301. https://doi.org/10.1179/016164105X25234
  40. Sung J-H, Choi D-H, Kim D-H, Chun B-G, Choi S-H. White ginseng saponin upregulated the production of TNF-alpha, IL-1beta, and NO in primary cultures of mixed glial cells. J Ginseng Res 2004;28:120-6. https://doi.org/10.5142/JGR.2004.28.2.120
  41. Xing L, Jiang M, Dong L, Gao J, Hou Y, Bai G, Luo G. Cardioprotective effects of the YiQiFuMai injection and isolated compounds on attenuating chronic heart failure via $NF-{\kappa}B$ inactivation and cytokine suppression. J Ethnopharmacol 2013;148:239-45. https://doi.org/10.1016/j.jep.2013.04.019
  42. Nah S-Y, Park H-J, McCleskey EW. A trace component of ginseng that inhibits Ca2+ channels through a pertussis toxin-sensitive G protein. Proc Natl Acad Sci 1995;92:8739-43. https://doi.org/10.1073/pnas.92.19.8739
  43. Nah S-Y. Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors. Front Physiol 2014;5.
  44. Tachikawa E, Kudo K, Kashimoto T, Takahashi E. Ginseng saponins reduce acetylcholine-evoked Na+ influx and catecholamine secretion in bovine adrenal chromaffin cells. J Pharmacol Exp Ther 1995;273:629-36.
  45. Kudo K, Tachikawa E, Kashimoto T, Takahashi E. Properties of ginseng saponin inhibition of catecholamine secretion in bovine adrenal chromaffin cells. Eur J Pharmacol 1998;341:139-44. https://doi.org/10.1016/S0014-2999(97)01350-2
  46. Kim HS, Lee JH, Goo YS, Nah SY. Effects of ginsenosides on Ca2+ channels and membrane capacitance in rat adrenal chromaffin cells. Brain Res Bull 1998;46:245-51. https://doi.org/10.1016/S0361-9230(98)00014-8
  47. Choi S, Jung S-Y, Lee J-H, Sala F, Criado M, Mulet J, Valor LM, Sala S, Engel AG, Nah S-Y. Effects of ginsenosides, active components of ginseng, on nicotinic acetylcholine receptors expressed in Xenopus oocytes. Eur J Pharmacol 2002;442:37-45. https://doi.org/10.1016/S0014-2999(02)01508-X
  48. Kimura T, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK. Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors. Gen Pharmacol 1994;25:193-9. https://doi.org/10.1016/0306-3623(94)90032-9
  49. Choi S, Jung SY, Ko YS, Koh SR, Rhim H, Nah SY. Functional expression of a novel ginsenoside Rf binding protein from rat brain mRNA in Xenopus laevis oocytes. Mol Pharmacol 2002;61:928-35. https://doi.org/10.1124/mol.61.4.928
  50. Nah SY, Kim DH, Rhim H. Ginsenosides: are any of them candidates for drugs acting on the central nervous system? CNS Drug Rev 2007;13:381-404. https://doi.org/10.1111/j.1527-3458.2007.00023.x

Cited by

  1. Chinese Herbal Medicine for the Treatment of Depression: Effects on the Neuroendocrine-Immune Network vol.14, pp.1, 2020, https://doi.org/10.3390/ph14010065
  2. Tetragonia tetragonioides Relieves Depressive-Like Behavior through the Restoration of Glial Loss in the Prefrontal Cortex vol.2021, 2021, https://doi.org/10.1155/2021/8888841
  3. A Review of the Pharmacological Characteristics of Vanillic Acid vol.11, pp.2, 2021, https://doi.org/10.22270/jddt.v11i2-s.4823
  4. The effect of ginsenosides on depression in preclinical studies: A systematic review and meta-analysis vol.45, pp.3, 2020, https://doi.org/10.1016/j.jgr.2020.08.006
  5. The promising therapeutic potentials of ginsenosides mediated through p38 MAPK signaling inhibition vol.7, pp.11, 2020, https://doi.org/10.1016/j.heliyon.2021.e08354