Journal of Ginseng Research

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

DOI QR Code

Effects of Korea Red Ginseng Total Saponin on Repeated Unpredictable Stress-induced Changes of Proliferation of Neural Progenitor Cells and BDNF mRNA Expression in Adult Rat Hippocampus

반복 스트레스에 의한 흰쥐 해마조직내 신경전구세포의 생성과 brain-derived neurotrophic factor (BDNF) mRNA 발현 변동에 미치는 고려홍삼 사포닌의 반복 투여 효과

  • Kim, Dong-Hoon (Department of Pharmacology, College of Medicine, Korea University) ;
  • Kwak, Kyu-Hwan (Department of Neurology, College of Medicine, Cheju National University) ;
  • Lee, Kuem-Ju (Department of Pharmacology, College of Medicine, Korea University) ;
  • Kim, Sung-Jin (Department of Pharmacology, College of Medicine, Korea University) ;
  • Shin, You-Chan (Department of Pharmacology, College of Medicine, Korea University) ;
  • Chun, Boe-Gwun (Department of Pharmacology, College of Medicine, Korea University) ;
  • Shin, Kyung-Ho (Department of Pharmacology, College of Medicine, Korea University)
  • Published : 2004.06.01
Download PDF
⟨ Previous Next ⟩

Abstract

Korean red ginseng is known to have anti-stress and memory enhancing effects. Recent studies suggested that stress-induced inhibition of adult neurogenesis in hippocampus may contribute, in part, to decreased negative feedback inhibition of HPA axis. In order to elucidate the mechanism of Korean red ginseng in anti-stress and memory enhancing effects, we observed the effects of repeated treatment of Korean red ginseng total saponin (GTS, 50 mg/kg, i.p.) in response to repeated unpredictable stress for 10 days. Male Sprague-Dawley rats (230 - 260 g) received with either GTS (50 mg/kg, i.p.) or vehicle (1 ml/kg, i.p.) 1 h before stress for 10 days. Rats were injected with bromodeoxyuridine (BrdU, 50 mg/kg, i.p.) 16-18 he after last stress procedure, and were sacrificed 2 hr later by perfusion. Immunohistochemistry of BrdU was done to measure proliferation of neural progenitor cells in hippocampus, which was used as an index of neurogenesis. Repeated GTS treatment for 10 days increased neurogenesis in subgranular zone area of dentate gyrus (SGZ), but not hilus, compared with vehicle-treated rats. Repeated unpredictable stress did not affect the neurogenesis compared with controls, while repeated GTS treatment increased neurogenesis in SGZ in repeated unpredictable stress-exposed group. BDNF mRNA was also measured in subregions of hippocampus by in situ hybridization. BDNF mRNA expression in CA3 and CA1 pyramidal cell layer was increased by repeated GTS treatment but not in dentate granule cell layer. Repeated unpredictable stresses significantly decreased BDNF mRNA expression in all subregions of hippocampus, but repeated GTS treatment did not prevent stress-induced BDNF mRNA downregulation. Given that repeated GTS treatment increased proliferation of neural progenitor cells in repeated unpredictable stress-exposed rats in the presence of decreased BDNF mRNA expression in dentate granule cell layer, it raise the possibility that BDNF may not playa significant role in GTS-mediated increase of neurogenesis in adult rat hippocampus. Also, these results suggest that repeated GTS treatment increased neurogenesis of SGZ and BDNF mRNA expression, which may account for memory enhancing effect of Korean red ginseng. In addition, repeated GTS treatment appears not to have anti-stress effects in terms of neurotrophin, but GTS-mediated increase of neurogenesis in hippocampus may contribute to increase negative feedback inhibition of HPA axis.

본 연구 결과를 통하여 홍삼 성분인 고려홍삼 사포닌을 반복 투여시 흰쥐 해마 SGZ 부위의 신경전구세포 생성이 유의하게 증가되었으며, 이와 같은 경향은 반복 스트레스에 노출되어도 유지되었다. 또한 스트레스를 가하지 않은 흰쥐에서 고려홍삼 사포닌 반복 투여시 해마 CA3와 CA1 부위에서 BDNF mRNA의 발현이 증가되었으나, 반복 스트레스를 가한 흰쥐의 CA3와 CA1부위에서 BDNF mRNA의 감소를 차단하지는 못하였다. 따라서 고려홍삼 사포닌 반복 처치에 의한 해마 신경전구세포의 생성에 BDNF 보다는 다른 요인이 관여할 가능성이 클 것으로 추정된다.

Keywords

References

  1. Petkov, V.D. and Mosharrof, A.H. ; Effects of standardized ginseng extract on learning, memory and physical capabiloties. Am J Chin Med. 15(1-2), 19-20 (1987)
  2. Altman, L. and Das, G.D. : Autoradiographic and histological evidence of postantal hippocampal neurogenesis in rats. Comp Neurol. 124(3), 319-335 (1965) https://doi.org/10.1002/cne.901240303
  3. Gould, E. and McEwen, B. S.: Neuronal birth and death. Curr Opin Neurobiol. 3(5), 676-682 (1993) https://doi.org/10.1016/0959-4388(93)90138-O
  4. Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. and Fuchs, E. : Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 17(7), 2492-2498 (1997)
  5. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA. 97(20), 11032-11037 https://doi.org/10.1073/pnas.97.20.11032
  6. Fuchs, E., Flugge, G., Ohl, F., Lucassen, P., Vollmann-HonsDorf, G. K. and https://doi.org/10.1016/S0031-9384(01)00497-8
  7. Kempermann, G., Kuhn, H.G. and Gage, F.H. : More hippocampal neurons in adult mice living in an enriched enviroment. Nature. 386(6624), 493-495 (1997) https://doi.org/10.1038/386493a0
  8. Herman, J.P.and Cullinan, W.E. : Neurocircuitry of stress:central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 20(2), 78-84 (1997) https://doi.org/10.1016/S0166-2236(96)10069-2
  9. Jacobson, L. and Sapolsky, R. : The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev. 12(2), 118-134 (1991) https://doi.org/10.1210/edrv-12-2-118
  10. Arango, C., Breier, A., McManhon, R., Carpenter, W. T., Jr. and Buchanan, R. W. : The relationship of clozapine and haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes. Am J Psychiatry. 160(8), 1421-1427 (2003) https://doi.org/10.1176/appi.ajp.160.8.1421
  11. Duman, R. S., Heninger, G. R. and Nestler, E. J. : A molecular and cellular theory of depression. Arch Gen Psychiatry. 54(7), 597-606 (1997) https://doi.org/10.1001/archpsyc.1997.01830190015002
  12. McEwen, B. S., Magarinos, A. M. and Reagan, L. P. : Studies of hormone action in the hippocampal formation: possible relevance to depression and diabetes. J. Psychosom Res. 53(4), 883-890 (2002) https://doi.org/10.1016/S0022-3999(02)00307-0
  13. Jacobs, B. L., Praag, H. and Gage, F. H. : Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol psychiatry. 5(3), 262-269 (2000) https://doi.org/10.1038/sj.mp.4000712
  14. Duman, R. S., Malberg, J., Nakagawa, S. and D'Sa, C. : Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 48(8), 732-739 (2000) https://doi.org/10.1016/S0006-3223(00)00935-5
  15. Duman, R. S., Malberg, J. and Thome, J. : Neural plasticity to stress and antidepressant trement. Biological Psychiatry. 46(9), 1181-1191 (1999) https://doi.org/10.1016/S0006-3223(99)00177-8
  16. Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M. and Varon, S. : Distribution of brain-derived neurotrophic factor(BDNF) protein and mRNA in the normal adult rat CNS:evidence for anterograde axonal transport. J. Neurosci. 17(7), 2295-2313 (1997)
  17. Kitamura, T., Mishina, M. and Sugiyama, H. : Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. NeurosciRes. 47(1), 55-63 (2003) https://doi.org/10.1016/S0168-0102(03)00171-8
  18. Lee, J., Duan, W. and Mattson, M. P. : Evidence that brainderived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocanpus of adult mice. J. Neurochem. 82(6), 1376-1375 (2002) https://doi.org/10.1046/j.1471-4159.2002.01085.x
  19. Katoh-Semba, R., Asano, T., Ueda, H., Morishita, R., Takeuchi, I. K., Inaguma, Y. and Kato, K. : Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. Faseb J. 16(10), 1328-1330 (2002) https://doi.org/10.1096/fj.02-0143fje
  20. Kirschenbaum, B. and Goldman, S. A. : Brain-derived neurotrophic factor promotes the survival of neurons arising from the adult rat forebrain subependymal zone. Proc Natl Acad Sci USA. 92(1), 210-214 (1995) https://doi.org/10.1073/pnas.92.1.210
  21. Smith, M. A., Makio, S., Kvetnansky, R. and Post, R. M. : Effects of stress on neurotrophic factor expression in the rat brain. Ann Ny Acad Sci. 771, 234-239 (1995) https://doi.org/10.1111/j.1749-6632.1995.tb44684.x
  22. Ortiz, J., Fitzgerald, L. W., Lane, S., Terwilliger, R. and Nestler, E. J. : Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress. Neuropsychopharmacology. 14(6), 443-452 (1996) https://doi.org/10.1016/0893-133X(95)00152-4
  23. Ni, Y. G., Gold, S.J., Iredakem P.A., Terwilliger, R. Z., Duman, R. S. and Nestler, E. J. : Region-specific regulation of RGS4 (Regulator of G-protein-signaling protein type 4) in brain by stress and glucocorticoids: in vivo and in vitro studies. J. Neurosci. 19(10), 3674-3680 (1999)
  24. Eisch, A. J. and Nestler, E. J. : To be or not to be: adult neurogenesis and psychiatry. Clinical Neuroscience Research. 2(1-2), 93-108 (2002) https://doi.org/10.1016/S1566-2772(02)00011-7
  25. Tanapat, P., Galea, L. A. and Gould, E, : Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci. 16(3-4), 235-239 (1998) https://doi.org/10.1016/S0736-5748(98)00029-X
  26. Cameron, H. A., Tanapat, P. and Gould, E. : Adrenal steroids and N-methyl--aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience. 82(2), 349-354 (1997) https://doi.org/10.1016/S0306-4522(97)00303-5
  27. Tanapat, P., Hasting, N. B., Rydel, T. A., Galea, L. A. and Gould, E. : Ecposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormonedependent mechanism. J. Comp Neurol. 437(4), 496-504(2001) https://doi.org/10.1002/cne.1297
  28. Cameron, H. A. and Gould, E. : Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 61(2), 203-209 (1994) https://doi.org/10.1016/0306-4522(94)90224-0
  29. Nacger, J., Alonso-Llosa, G., Rosell, D. R. and McEwen, B.S. :NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiology of Aging. 24(2), 273-284 (2003) https://doi.org/10.1016/S0197-4580(02)00096-9
  30. Kempermann, G., Kuhn, H. G. and Gare, F. G. : Experience-induced neurogenesis in the senescent dentate gyrus. J. Neurosci. 18(9), 3206-3212 (1998)
  31. Kempermann, G., Gast, D. and Gage, F. H. : Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol. 52(2), 135-143 (2002) https://doi.org/10.1002/ana.10262
  32. Kuhn, H. G., Dickinson-Anson, H. and Gage, F. H. : Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16(6), 2027-2033 (1996)
  33. Cameron, H. A. and McKay, R. D. : Restoring production of hippocampal neurons in old age. Nat Neurosci. 2(10), 894-897 (1999) https://doi.org/10.1038/13197
  34. Montaron, M. F., Petry, K. G., Rodriguez, J. J., Marinelli, M., Aurousseau, C., Rougon, G., Le Moal M. and Abrous, D. N. : Adrenalectomy increases neurogenesis but not PSANCAM expression in aged dentate gyrus. Eur J Neurosci. 11(4), 1479-1485 (1999) https://doi.org/10.1046/j.1460-9568.1999.00579.x
  35. Cameron, H. A., Woolley, C. S. and Gould, E. : Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus. Brain Res. 611(2), 342-346 (1993) https://doi.org/10.1016/0006-8993(93)90524-Q
  36. Lim, B. V., Shin, M. C., Jang, M. H., Lee, T. H., Kim, Y. P., Kim,H.B., Lee, K. S., Kim, H., Kim, E. H. and Kim, C. J. : Ginseng radix increases cell proliferation in dentate gyrus of rats with streptozotocin-induced diabetes. Biol Pharm Bull. 25(12), 1550-1554 (2002) https://doi.org/10.1248/bpb.25.1550
  37. Kim, D. H., Moon, Y. S., Jung, J. S., Min, S. K., Son, B. K., Suh, H. W. and Song, D. K. : Effects of ginseng saponin administered intraperitoneally on the hypothalamo-pituitary-adrenal axis in mice. Neurosci Lett. 343(1), 62-66 (2003) https://doi.org/10.1016/S0304-3940(03)00300-8
  38. Yuan, W. X., Wu, X. J., Yang, F. X., Sbang, X. H. and Zhang, L. L. : Effects of ginseng root saponins on brain monoamines and serum corticosterone in heat-stressed mice. Zhongguo Yao Li Xue Bao. 10(6), 492-496 (1989)
  39. Czeh, B., Welt, T., Fisher A. K., Erhardt, A., Schmitt, W., Muller, M. B., Toschi, N., Fuchs, E. and Keck, M. E. : Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis. Biol Psychiatry. 52(11), 1057-1065 (2002) https://doi.org/10.1016/S0006-3223(02)01457-9
  40. Issa, A. M., Rowe, W., Gauthier, S. and Meaney, M. J. : Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J. Neurosci. 10(10), 3247-3254 (1990)
  41. Rhim, H. : The Effects of Ginsenoside Rg3 as a Potent Inhibitor of Ca2+ Channels and NMDA-gated Channels in the Peripheral and Central Nervous Systems. J. Ginseng Res. 27, 120-128 (2003)
  42. Takahashi, J., Palmer, T. D. and Gage, F. H. : Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J. Neurobiol. 38(1), 65-81 (1999) https://doi.org/10.1002/(SICI)1097-4695(199901)38:1<65::AID-NEU5>3.0.CO;2-Q
  43. Memberg, S. P. and Hall, A. K. : Proliferation, differentiation, and survival of rat sensory neuron precursors in vitro require specific trophic factors. Mol cell Neurosci. 6(4), 323-335 (1995) https://doi.org/10.1006/mcne.1995.1025
  44. Takei, Y., Yamamoto, T., Higashira, H. and Hayashi, K. : Identification of basic fibroblast growth factor-like immunoreactivity in panax ginseng extract : investigation of its molecular properties. Biosci Biotechnol Biochem. 60(4), 584-588 (1996) https://doi.org/10.1271/bbb.60.584
  45. Tao, Y., Black, I. B. and DiCicco-Bloom, E. : Neurogenesis in neonatal rat brain is regulated by peripheral injection of basic fibroblast growth factor (bFGF). J. Comp Neurol. 376(4), 653-663 (1999) https://doi.org/10.1002/(SICI)1096-9861(19961223)376:4<653::AID-CNE11>3.0.CO;2-N
  46. Wagner, J. P., Black, I. B. and DiCicco-Bloom, E. : Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J. Neurosci. 19(14), 6006-6016 (1999)
  47. Cheng, Y., Black, I. B. and DiCicco-Bloom, E. : Hippocampal granule neuron Production and population size are regulated by levels of bFGE. Eur. J. Neurosci. 15(1), 3-12 (2002) https://doi.org/10.1046/j.0953-816x.2001.01832.x
  48. Zhao, S., Jiang, Y. and Luo, Q. : [Relation between BDNF and synaptic reorganization of hippocampal mossy fibers]. Zhonghua Yi Xue Za Zhi. 81(5), 283-287 (2001)
  49. Korte, M., Carroll, P., Wolf, E., Brem, G., Thoenen, H. and Bonhoeffer, T.: Hippocampal long brain-derived neurotrophion is impaired in mice lacking brain-derived neurotrophin factor. Proc Natl Acad Sci USA. 92(19), 8856-8860 (1995). https://doi.org/10.1073/pnas.92.19.8856
  50. Korte, M., Griesbeck, O., Gravel, C., Carroll, P., Staiger, V., Thoenen, H. and Bonhoeffer, T.: Virus-mediated genetransfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophin factor mutant mine.Proc Natl Acad Sci USA. 93(22), 12547-12552 (1996) https://doi.org/10.1073/pnas.93.22.12547
  51. Patterson, S. L., Abel, T., Deuel, T. A., Martin, K. C., Rose, J. C. and Kandel, E. R. : Recombinant BDNF Rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 16(6), 1137-1145 (1996) https://doi.org/10.1016/S0896-6273(00)80140-3

Cited by

  1. Saponin Composition and Physico-Chemical Properties of Korean Red Ginseng Extract as Affected by Extracting Conditions vol.37, pp.2, 2008, https://doi.org/10.3746/jkfn.2008.37.2.256
  2. Effect of Red Ginseng Extracts on the Qualities of Low Salt and Low Fat Pork Sausage vol.31, pp.4, 2011, https://doi.org/10.5851/kosfa.2011.31.4.588
  3. Oral Toxicity Study on the 90-day Repeated-dose of 50 kGy Irradiated Methanol Extract Powder of Red Ginseng vol.40, pp.6, 2011, https://doi.org/10.3746/jkfn.2011.40.6.824
  4. Standardization of ginseng processing for maximizing the phytonutrients of ginseng vol.22, pp.S1, 2013, https://doi.org/10.1007/s10068-013-0070-4
  5. A Study on the Amendment Scheme of Ginsenoside Content Standard Regulation for Red Ginseng Products in Korea vol.28, pp.1, 2013, https://doi.org/10.13103/JFHS.2013.28.1.024
  6. Comparative Study on Immuno-Enhancing Effects of Red Ginseng Fractions vol.43, pp.11, 2014, https://doi.org/10.3746/jkfn.2014.43.11.1665
  7. Saponin Contents and Physicochemical Properties of Red Ginseng Extract Pouch Products Collected from Ginseng Markets in Korea vol.39, pp.11, 2010, https://doi.org/10.3746/jkfn.2010.39.11.1660
  8. Effects of Size Adjusted with Red Ginseng Powders on Quality of Fish Pastes vol.41, pp.10, 2012, https://doi.org/10.3746/jkfn.2012.41.10.1448