DOI QR코드

DOI QR Code

Effect of Ginsenoside Re on Depression- and Anxiety-Like Behaviors and Cognition Memory Deficit Induced by Repeated Immobilization in Rats

  • Lee, Bom-Bi (Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University) ;
  • Shim, In-Sop (Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University) ;
  • Lee, Hye-Jung (Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University) ;
  • Hahm, Dae-Hyun (Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University)
  • Received : 2011.12.21
  • Accepted : 2012.01.04
  • Published : 2012.05.28

Abstract

In this study, we assessed the effects of ginsenoside Re (GRe) administration on repeated immobilization stress-induced behavioral alterations using the forced swimming test (FST), the elevated plus maze (EPM), and the active avoidance conditioning test (AAT). Additionally, we examined the effect of GRe on the central adrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brain. Male rats received 10, 20, or 50 mg/kg GRe (i.p.) 30 min before daily exposures to repeated immobilization stress (2 h/day) for 10 days. Activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to repeated immobilization was confirmed by measuring serum levels of corticosterone (CORT) and the expression of corticotrophin-releasing factor (CRF) in the hypothalamus. Repeated immobilization stress increased immobility in the FST and reduced open-arm exploration in the EPM test. It also increased the probability of escape failures in the AAT test, indicating a reduced avoidance response. Daily administration of GRe during the repeated immobilization stress period significantly inhibited the stress-induced behavioral deficits in these behavioral tests. Administration of GRe also significantly blocked the increase in TH expression in the locus coeruleus (LC) and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of GRe prior to immobilization stress significantly improved helpless behaviors and cognitive impairment, possibly through modulating the central noradrenergic system in rats. These findings suggest that GRe may be a useful agent for treating complex symptoms of depression, anxiety, and cognitive impairment.

Keywords

References

  1. Bhatnagar, S., J. B. Mitchell, K. Betito, P. Boksa, and M. J. Meaney. 1995. Effects of chronic intermittent cold stress on pituitary adrenocortical and sympathetic adrenomedullary functioning. Physiol. Behav. 57: 633-639. https://doi.org/10.1016/0031-9384(94)00161-8
  2. Bignante, E. A., P. A. Rodriguez Manzanares, E. C. Mlewski, M. E. Bertotto, D. F. Bussolino, G. Paglini, and V. A. Molina. 2008. Involvement of septal Cdk5 in the emergence of excessive anxiety induced by stress. Eur. Neuropsychopharmacol. 18: 578-588. https://doi.org/10.1016/j.euroneuro.2008.02.007
  3. Bondi, C. O., J. D. Jett, and D. A. Morilak. 2010. Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 34: 913-923. https://doi.org/10.1016/j.pnpbp.2010.04.016
  4. Carvalho, M. C., S. Masson, M. L. Brandao, and M. A. de Souza Silva. 2008. Anxiolytic-like effects of substance P administration into the dorsal, but not ventral, hippocampus and its influence on serotonin. Peptides 29: 1191-1200. https://doi.org/10.1016/j.peptides.2008.02.014
  5. Choi, J. H., S. Y. Yoon, E. J. Choi, Y. S. Ryu, H. S. Ko, D. S. Yim, et al. 2007. Anxiolytic and antidepressant activities of ginsenoside Rb1. Biomol. Ther. (Seoul) 15: 27-32.
  6. Chotiwat, C. and R. B. Harris. 2008. Antagonism of specific corticotropin-releasing factor receptor subtypes selectively modifies weight loss in restrained rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295: R1762-R1773. https://doi.org/10.1152/ajpregu.00196.2008
  7. Cryan, J. F. and A. Holmes. 2005. The ascent of mouse: Advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4: 775-790. https://doi.org/10.1038/nrd1825
  8. Dal-Zotto, S., O. Marti, and A. Armario. 2000. Influence of single or repeated experience of rats with forced swimming on behavioural and physiological responses to the stressor. Behav. Brain Res. 114: 175-181. https://doi.org/10.1016/S0166-4328(00)00220-5
  9. Daniels, W. M., L. Richter, and D. J. Stein. 2004. The effects of repeated intra-amygdala CRF injections on rat behavior and HPA axis function after stress. Metab. Brain Dis. 19: 15-23.
  10. Elizalde, N., F. J. Gil-Bea, M. J. Ramírez, B. Aisa, B. Lasheras, J. Del Rio, and R. M. Tordera. 2008. Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: Effect of antidepressant treatment. Psychopharmacology (Berl) 199: 1-14. https://doi.org/10.1007/s00213-007-1035-1
  11. Fan, J. M., X. O. Chen, H. Jin, and J. Z. Du. 2009. Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic-pituitary- adrenal axis and induces anxiety-like behavior in adult male rat offspring. Neuroscience 159: 1363-1373. https://doi.org/10.1016/j.neuroscience.2009.02.009
  12. Fiebich, B. L., R. Knorle, K. Appel, T. Kammler, and G. Weiss. 2011. Pharmacological studies in an herbal drug combination of St. John's Wort (Hypericum perforatum) and passion flower (Passiflora incarnata): In vitro and in vivo evidence of synergy between Hypericum and Passiflora in antidepressant pharmacological models. Fitoterapia 82: 474-480. https://doi.org/10.1016/j.fitote.2010.12.006
  13. Getachew, B., S. R. Hauser, R. E. Taylor, and Y. Tizabi. 2008. Desipramine blocks alcohol-induced anxiety- and depressive-like behaviors in two rat strains. Pharmacol. Biochem. Behav. 91: 97-103. https://doi.org/10.1016/j.pbb.2008.06.016
  14. Grauer, S. M., V. L. Pulito, R. L. Navarra, M. P. Kelly, C. Kelley, R. Graf, et al. 2009. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J. Pharmacol. Exp. Ther. 331: 574-590. https://doi.org/10.1124/jpet.109.155994
  15. Gregus, A., A. J. Wintink, A. C. Davis, and L. E. Kalynchuk. 2005. Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav. Brain Res. 156: 105-114. https://doi.org/10.1016/j.bbr.2004.05.013
  16. Herrera-Guzman, I., J. E. Herrera-Abarca, E. Gudayol-Ferre, D. Herrera-Guzman, L. Gomez-Carbajal, M. Pena-Olvira, et al. 2010. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res. 177: 323-329. https://doi.org/10.1016/j.psychres.2010.03.006
  17. Jin, S. H., J. K. Park, K. Y. Nam, S. N. Park, and N. P. Jung. 1999. Korean red ginseng saponins with low ratios of protopanaxadiol and protopanaxatriol saponin improve scopolamine-induced learning disability and spatial working memory in mice. J. Ethnopharmacol. 66: 123-129. https://doi.org/10.1016/S0378-8741(98)00190-1
  18. Johnson, S. A., N. M. Fournier, and L. E. Kalynchuk. 2006. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav. Brain Res. 168: 280-288. https://doi.org/10.1016/j.bbr.2005.11.019
  19. Jovanovski, E., A. Jenkins, A. G. Dias, V. Peeva, J. Sievenpiper, J. T. Arnason, et al. 2010. Effects of Korean red ginseng (Panax ginseng C. A. Mayer) and its isolated ginsenosides and polysaccharides on arterial stiffness in healthy individuals. Am. J. Hypertens. 23: 469-472. https://doi.org/10.1038/ajh.2010.5
  20. Kim, N. H., K. Y. Kim, H. J. Jeong, and H. M. Kim. 2011. Antidepressant-like effect of altered Korean red ginseng in mice. Behav. Med. 37: 42-46. https://doi.org/10.1080/08964289.2011.566591
  21. Kim, J. H., S. A. Kang, S. M. Han, and I. Shim. 2009. Comparison of the antiobesity effects of the protopanaxadioland protopanaxatriol-type saponins of red ginseng. Phytother. Res. 23: 78-85. https://doi.org/10.1002/ptr.2561
  22. Klenerova, V., I. Krejci, P. Sida, Z. Hlinak, and S. Hynie. 2010. Oxytocin and carbetocin ameliorating effects on restraint stress-induced short- and long-term behavioral changes in rats. Neuro. Endocrinol. Lett. 31: 622-630.
  23. Maccari, S. and S. Morley-Fletcher. 2007. Effects of prenatal restraint stress on the hypothalamus-pituitary-adrenal axis and related behavioural and neurobiological alterations [Review]. Psychoneuroendocrinology 32: S10-S15.
  24. Magarinos, A. M., C. J. Li, J. Gal Toth, K. G. Bath, D. Jing, F. S. Lee, and B. S. McEwen. 2011. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 21: 253-264. https://doi.org/10.1002/hipo.20744
  25. Marks, W., N. M. Fournier, and L. E. Kalynchuk. 2009. Repeated exposure to corticosterone increases depression-like behavior in two different versions of the forced swim test without altering nonspecific locomotor activity or muscle strength. Physiol. Behav. 98: 67-72. https://doi.org/10.1016/j.physbeh.2009.04.014
  26. Mineka, S. and R. Zinbarg. 2006. A contemporary learning theory perspective on the etiology of anxiety disorders: It's not what you thought it was. Am. Psychol. 61: 10-26.
  27. Mochizuki, D., R. Tsujita, S. Yamada, K. Kawasaki, Y. Otsuka, S. Hashimoto, et al. 2002. Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats. Psychopharmacology (Berl) 162: 323-332. https://doi.org/10.1007/s00213-002-1111-5
  28. Naert, G., G. Ixart, T. Maurice, L. Tapia-Arancibia, and L. Givalois. 2011. Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress. Mol. Cell Neurosci. 46: 55-66. https://doi.org/10.1016/j.mcn.2010.08.006
  29. Nestler, E. J., M. Barrot, R. J. DiLeone, A. J. Eisch, S. J. Gold, and L. M. Monteggia. 2002. Neurobiology of depression. Neuron 34: 13-25. https://doi.org/10.1016/S0896-6273(02)00653-0
  30. Osterhout, C. A., C. R. Sterling, D. M. Chikaraishi, and A. W. Tank. 2005. Induction of tyrosine hydroxylase in the locus coeruleus of transgenic mice in response to stress or nicotine treatment: Lack of activation of tyrosine hydroxylase promoter activity. J. Neurochem. 94: 731-741. https://doi.org/10.1111/j.1471-4159.2005.03222.x
  31. Padovan, C. M. and F. S. Guimaraes. 2000. Restraint-induced hypoactivity in an elevated plus-maze. Braz. J. Med. Biol. Res. 33: 79-83.
  32. Park, H. J., H. S. Shim, H. Kim, K. S. Kim, H. Lee, D. H. Hahm, and I. Shim. 2010. Effects of Glycyrrhizae Radix on repeated restraint stress-induced neurochemical and behavioral responses. Korean J. Physiol. Pharmacol. 14: 371-376. https://doi.org/10.4196/kjpp.2010.14.6.371
  33. Patel, S., C. T. Roelke, D. J. Rademacher, W. E. Cullinan, and C. J. Hillard. 2004. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145: 5431-5438. https://doi.org/10.1210/en.2004-0638
  34. Paxinos, G. and C. Watson. 1986. The Rat Brain in Stereotaxic Coordinates, pp. 54-85. Academic Press, NY.
  35. Sandi, C., J. J. Merino, M. I. Cordero, K. Touyarot, and C. Venero. 2001. Effects of chronic stress on contextual fear conditioning and the hippocampal expression of the neural cell adhesion molecule, ITS polysialylation and L1. Neuroscience 102: 329-339. https://doi.org/10.1016/S0306-4522(00)00484-X
  36. Sandstrom, N. J. and S. R. Hart. 2005. Isolation stress during the third postnatal week alters radial arm maze performance and corticosterone levels in adulthood. Behavior. Brain Res. 156: 289-296. https://doi.org/10.1016/j.bbr.2004.05.033
  37. Savaskan, E., S. E. Muller, A. Bohringer, A. Schulz, and H. Schachinger. 2008. Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients. Int. J. Neuropsychopharmacol. 11: 381-388.
  38. Sevgi, S., M. Ozek, and L. Eroglu. 2003. L-NAME prevents anxiety-like and depression-like behavior in rats exposed to restraint stress. Methods Find. Exp. Clin. Pharmacol. 28: 95-99.
  39. Siuciak, J. A., D. R. Lewis, S. J. Wiegand, and R. M. Lindsay. 1997. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56: 131-137. https://doi.org/10.1016/S0091-3057(96)00169-4
  40. Tanaka, M. and G. Telegdy. 2008. Involvement of adrenergic and serotonergic receptors in antidepressant-like effect of urocortin 3 in a modified forced swimming test in mice. Brain Res. Bull. 77: 301-305. https://doi.org/10.1016/j.brainresbull.2008.08.012
  41. Tanke, M. A., D. S. Fokkema, B. Doornbos, F. Postema, and J. Korf. 2008. Sustained release of corticosterone in rats affects reactivity, but does not affect habituation to immobilization and acoustic stimuli. Life Sci. 83: 135-141. https://doi.org/10.1016/j.lfs.2008.05.015
  42. Tode, T., Y. Kikuchi, J. Hirata, T. Kita, H. Nakata, and I. Nagata. 1999. Effect of Korean red ginseng on psychological functions in patients with severe climacteric syndromes. Int. J. Gynaecol. Obstet. 67: 169-174. https://doi.org/10.1016/S0020-7292(99)00168-X
  43. Tsigos, C. and G. P. Chrousos. 2002. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53: 865-871. https://doi.org/10.1016/S0022-3999(02)00429-4
  44. Ulrich-Lai, Y. M., W. Xie, J. T. Meij, C. M. Dolgas, L. Yu, and J. P. Herman. 2006. Limbic and HPA axis function in an animal model of chronic neuropathic pain. Physiol. Behav. 88: 67-76. https://doi.org/10.1016/j.physbeh.2006.03.012
  45. Vieira, C., T. C. De Lima, P. Carobrez Ade, and C. Lino-de-Oliveira. 2008. Frequency of climbing behavior as a predictor of altered motor activity in rat forced swimming test. Neurosci. Lett. 445: 170-173. https://doi.org/10.1016/j.neulet.2008.09.001
  46. Vyas, A., R. Mitra, B. S. Rao, and S. Chattarji. 2002. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 2: 6810-6818.
  47. Walesiuk, A. and J. J. Braszko. 2009. Preventive action of Ginkgo biloba in stress- and corticosterone-induced impairment of spatial memory in rats. Phytomedicine 16: 40-46. https://doi.org/10.1016/j.phymed.2007.04.012
  48. Walf, A. A. and C. A. Frye. 2007. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat. Protoc. 2: 322-328. https://doi.org/10.1038/nprot.2007.44
  49. Wang, Y. Z., J. Chen, S. F. Chu, Y. S. Wang, X. Y. Wang, N. H. Chen, and J. T. Zhang. 2009. Improvement of memory in mice and increase of hippocampal excitability in rats by ginsenoside Rg1's metabolites ginsenoside Rh1 and protopanaxatriol. J. Pharmacol. Sci. 109: 504-510. https://doi.org/10.1254/jphs.08060FP
  50. Wong, M. L. and J. Licinio. 2001. Research and treatment approaches to depression. Nat. Rev. Neurosci. 2: 343-351. https://doi.org/10.1038/35072566
  51. Xing, B., Y. Zhao, H. Zhang, Y. Dang, T. Chen, J. Huang, and Q. Luo. 2011. Microinjection of valproic acid into the ventrolateral orbital cortex exerts an antidepressant-like effect in the rat forced swim test. Brain Res. Bull. 85: 153-157. https://doi.org/10.1016/j.brainresbull.2011.03.007
  52. Yamada, N., H. Araki, and H. Yoshimura. 2011. 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) 216: 589-599. https://doi.org/10.1007/s00213-011-2252-1
  53. Yan, B., J. He, H. Xu, Y. Zhang, X. Bi, S. Thakur, et al. 2007. Quetiapine attenuates the depressive and anxiolytic-like behavioural changes induced by global cerebral ischemia in mice. Behav. Brain Res. 182: 36-41. https://doi.org/10.1016/j.bbr.2007.05.002

Cited by

  1. Effects of ginsenoside Re on LPS-induced inflammatory mediators in BV2 microglial cells vol.12, pp.None, 2012, https://doi.org/10.1186/1472-6882-12-196
  2. Chronic Administration of Baicalein Decreases Depression-Like Behavior Induced by Repeated Restraint Stress in Rats vol.17, pp.5, 2012, https://doi.org/10.4196/kjpp.2013.17.5.393
  3. Ginsenoside Rg3 Alleviates Lipopolysaccharide-Induced Learning and Memory Impairments by Anti-Inflammatory Activity in Rats vol.21, pp.5, 2013, https://doi.org/10.4062/biomolther.2013.053
  4. Morphological Characterization, Chemical Components, and Biofunctional Activities ofPanax ginseng, Panax quinquefolium, andPanax notoginsengRoots: A Comparative Study vol.30, pp.2, 2012, https://doi.org/10.1080/87559129.2014.883631
  5. Behavioural screening of zebrafish using neuroactive traditional Chinese medicine prescriptions and biological targets vol.4, pp.None, 2012, https://doi.org/10.1038/srep05311
  6. Polygala tenuifolia prevents anxiety-like behaviors in mice exposed to repeated restraint stress vol.19, pp.1, 2015, https://doi.org/10.1080/19768354.2014.982176
  7. Myricetin Attenuates Depressant-Like Behavior in Mice Subjected to Repeated Restraint Stress vol.16, pp.12, 2012, https://doi.org/10.3390/ijms161226102
  8. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder vol.70, pp.2, 2016, https://doi.org/10.1007/s11418-015-0943-3
  9. Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test vol.2016, pp.None, 2012, https://doi.org/10.1155/2016/5098591
  10. Comparison of microwave‐assisted and heat reflux extraction techniques for the extraction of ten major compounds from Zibu Piyin Recipe using ultra high performance liquid chromatography with ta vol.39, pp.5, 2012, https://doi.org/10.1002/jssc.201501033
  11. Neuroprotective effect of ginsenoside Rg1 prevents cognitive impairment induced by isoflurane anesthesia in aged rats via antioxidant, anti-inflammatory and anti-apoptotic effects mediated by the PI3K vol.14, pp.3, 2016, https://doi.org/10.3892/mmr.2016.5556
  12. Botanicals as Modulators of Neuroplasticity: Focus on BDNF vol.2017, pp.None, 2017, https://doi.org/10.1155/2017/5965371
  13. White Ginseng Protects Mouse Hippocampal Cells Against Amyloid‐Beta Oligomer Toxicity vol.31, pp.3, 2012, https://doi.org/10.1002/ptr.5776
  14. Ginsenosides: A Potential Neuroprotective Agent vol.2018, pp.None, 2018, https://doi.org/10.1155/2018/8174345
  15. 전투 스트레스 및 피로 완화 약물 탐색을 위한 생체지표 vol.21, pp.2, 2018, https://doi.org/10.9766/kimst.2018.21.2.246
  16. Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology vol.23, pp.4, 2012, https://doi.org/10.3390/molecules23040940
  17. Ginsenoside Drug Nanocomposites Prepared by the Aerosol Solvent Extraction System for Enhancing Drug Solubility and Stability vol.10, pp.3, 2012, https://doi.org/10.3390/pharmaceutics10030095
  18. Active ginseng components in cognitive impairment: Therapeutic potential and prospects for delivery and clinical study vol.9, pp.71, 2018, https://doi.org/10.18632/oncotarget.26035
  19. Direct and indirect evidences of BDNF and NGF as key modulators in depression: role of antidepressants treatment vol.129, pp.3, 2019, https://doi.org/10.1080/00207454.2018.1527328
  20. Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis vol.12, pp.4, 2020, https://doi.org/10.3390/nu12040901
  21. Ginsenoside Re protects against chronic restraint stress‐induced cognitive deficits through regulation of NLRP3 and Nrf2 pathways in mice vol.35, pp.5, 2012, https://doi.org/10.1002/ptr.6947
  22. The effect of ginsenosides on depression in preclinical studies: A systematic review and meta-analysis vol.45, pp.3, 2012, https://doi.org/10.1016/j.jgr.2020.08.006