Ginseng radix Suppresses Ischemia-induced Increase in c-Fos Expression and Apoptosis in the Hippocampal CA1 Region in Gerbils

  • Park, Keung-Ryol (Departments of Physiology, College of Oriental Medicine, Kyungwon University) ;
  • Jang, Mi-Hyeon (Departments of Physiology, College of Medicine, Kyung Hee University) ;
  • Kim, Chang-Ju (Departments of Physiology, College of Medicine, Kyung Hee University) ;
  • Lee, Choong-Yeol (Departments of Physiology, College of Oriental Medicine, Kyungwon University)
  • Published : 2005.02.25


Ginseng radix, the root of Panax ginseng C.A.Meyer (Araliaceae), has traditionally been used for the treatment of various disorders including cerebrovascular accident (CVA). In the present study, the effect of Ginseng radix on c-Fos expression and apoptosis in the hippocampal CA1 region of gerbils following transient global ischemia was investigated via immunohistochemistry for c-Fos and caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Enhanced c-Fos-, TUNEL-, and caspase-3-positivities were detected in the hippocampal CA1 region in ischemic gerbils. Administration of the aqueous extract of Ginseng radix suppressed this ischemia-induced increment in the numbers of c-Fos-, TUNEL-, and caspase-3-positive cells. These results suggest that Ginseng radix has an inhibitive effect on the induction of c-Fos expression and apoptosis seen following transient global ischemia.


  1. Grillis, C.N. Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 54, 1-8, 1997.
  2. Sugaya, A., Yuzurihara, M., Tsuda, T., Yasuda, K., Kajiwara, K., Sugaya, E. Proliferative effect of ginseng saponin on neurite extention of primary cultured neurons of the rat cerebral cortex. J Ethnopharmcol 22, 173-181, 1988.
  3. Zhang, D., Yasuda, T., Yu, Y., Zhong, P., Kawabata, T., Ma, Y., Okada, S. Ginseng extract scavenges hydroxyl radical and protects unsaturated fatty acids from decomposition caused by iron-mediated lipid peroxidation. Free Rad Biol Med 20, 145-150, 1996.
  4. Colbourne, F., Sutherland, G.R., Auer, R.N. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 19, 4200-4210, 1999.
  5. Zeng, Y.S., Xu, Z.C., Co-existence of necrosis and apoptosis in rat hippocampus following transient forebrain ischemia. Neurosci Res 37, 113-125, 2000.
  6. Zhu, C., Wang, X., Hagberg, H., Blomgren, K. Correlation between caspase-3 activation and three different markers of DNA damage in neonatal cerebral hypoxia-ischemia. J Neurochem 75, 819-829, 2000.
  7. Cho, S., Park, EM., Kim, Y., Liu, N., Gal, J., Volpe, B.T., Joh, T.H. Early c-Fos induction after cerebral ischemia: a possible neuroprotective role. J Cereb Blood Metab 21, 550-556, 2001.
  8. Kiessling, M., Stumm, G, Xie, Y., Herdegen, T., Aguzzi, A., Bravo, R., Gass, P. Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia. J Cereb Blood Flow Metab 13: 914-924, 1993.
  9. Kogure, K., Kato, H. Altered gene expression in cerebral ischemia. Stroke 24, 2121-2127, 1993.
  10. Cubits, R.M., Burke, R.E., Casey-McIntosh. G., Bandele, A., Munell, F. Immediate-early gene induction after neuronal hypoxia-ischemia. Mol Brain Res 18, 228-238, 1993.
  11. Smeyne, R.J., Vendrell, M., Hayward, M., Baker, S.J., Miao. G., Schiling, K., Roberson, L.M., Curran, T., Morgan, J.I. Continuous c-Fos expression precedes programmed cell death in vivo. Nature 363, 166-169, 1993.
  12. Wessel, T.C., Joh, T.H., Volpe, B.T. in situ hybridization analysis of c-Fos and c-jun expression in the rat brain following transient global ischemia. Brain Res 567,231-240, 1991.
  13. Preston, G.A., Lyon, T.T., Yin, Y., Lang, J.E., Solomon, G., Annab, L., Srinivasan, D.G., Alcorata, D.A., Barrett, J.C. Induction of apoptosis by c-Fos protein. Mol Cell Biol 16, 211-218, 1996.
  14. Davoli, M.A., Ren, Y., Zhu, Y., Fourtounis. J., Jones, C., Robertson, G.S., Ng, G.Y.K., Xu, D. Automated analysis of global ischemia-induced CAl neuronal death using terminal UTP nick end labeling (TUNEL). J Neurosci Meth 115, 55-61, 2002.
  15. Yuan, J., Yankner, B.A. Apoptosis in the nervous system. Nature 407, 802-809, 2000.
  16. Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456-1462, 1995.
  17. Gavrieli, Y., Sherman, Y., Ben-Sasson, S.A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119, 493-501, 1992.
  18. Cohen, G.M. Caspases: the executioners of apoptosis. Biochem J 326, 1-16, 1997.
  19. Wen, T.C., Yoshimura, H., Matsuda, S., Lim, J.H., Sakanaka, M. Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute forebrain ischemia. Acta Neuropathol 91, 15-22, 1996.
  20. Liu, J., Solway, K., Messing, R.O., Sharp, F.R. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18, 7768-7778, 1998.
  21. Silveira, D.C., Sogawa, Y., Holmes, G.L. The expression of Fos following kainic acid-induced seizures is age-dependent. Eur J Neurosci 15, 329-344, 2002.
  22. Jang. M.H., Shin, M.C., Jung, S.B., Lee, T.H., Bahn, G.H., Kwon, Y., Kim, E.H., Kim, C.J. Alcohol and nicotine reduce cell proliferation and enhance apoptosis in dentate gyrus. Neuroreport 13, 1509-1513, 2002.
  23. Calvert, J.W., Yin, W., Patel, M., Badr, A., Mychaskiw, G., Parent, A.D., Zhang, J.H. Hyperbaric oxygenation prevented brain injury induced by hypoxia-ischemia in a neonatal rat model. Brain Res 951, 1-8, 2002.
  24. Jorgensen, M.B., Johansen, F.F., Diemer, N.H. Post-ischemic and kainic acid-induced c-fos protein expression in the rat hippocampus. Acta Neurol Scand 84, 352-356, 1991.
  25. Onodera, H., Kogure, K., Ono, Y., Igarashi, K., Kiyota, Y., Nagaoka, A. Proto-oncogene c-fos is transiently induced in the rat cerebral cortex after forebrain ischemia. Neurosci Lett 98, 101-104, 1989.
  26. Linnik, M.D., Miller, J.A., Sprinkle-Cavallo, J., Mason, P.J., Thompson, F.Y., Montgomery. L.R. and Schroeder, K.K. Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. Mol Brain Res 32, 116-124, 1995.
  27. Linnik, M.D., Zobrist, R.H., Hatfield, M.D. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24, 2002-2009, 1993.
  28. Kawase, M., Fujimura. M., Morita-Fujimura, Y.M., Chan, P.H. Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats: Implication of the failure of DNA repair in neuronal apoptosis. Stroke 30, 441-449, 1999.
  29. Pulera, M.R., Adams, L.M., Liu, H., Santos, D.G., Nishimura, R.N., Yang, F., Cole, G.M., Wasterlain, C.G. Apoptosis in a neonatal rat model of cerebral hypoxia-ischemia. Stroke 29, 2622-2630, 1988.
  30. Benchoua, A., Gugan, C., Couriaud, C., Hosseini, H., Sampao, N., Morin, D., Ontniente, B. Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21, 7127-7134, 2001.
  31. Gill, R., Sorian, M., Blomgren, K., Hagberg, H., Wybrecht, R., Miss, M.T., Hoefer, S., Adam, G., Niederhause, O., Kemp, J.A., Loetscher, H. Role of caspase-3 activation in cerebral ischemia-induced neurodegeneration in adult and neonatal brain. J Cereb Blood Metab 22, 420-430, 2001.
  32. Harrison, D.C., Davis, R.P., Bond, B.C., Campbell, C.A., James, M.F., Parsons, A.A., Philpott, K.L. Caspase mRNA expression in a rat model of focal cerebral ischemia. Mol Brain Res 89, 133-146, 2001.
  33. Maffei Facino, R., Carini, M., Aldini, G., Berti, F., Rossoni, G. Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion damage induced by hyperbaric oxygen: evidence for an antioxidant intervention. Planta Med 65, 614-619, 1999.
  34. Choi, S.R., Saji, H., Iida, Y., Magata, Y., Yokoyama, A. Ginseng pretreatment protects against transient global cerebral ischemia in the rat: measurement of local cerebral glucose utilization by [14C]deoxyglucose autoradiography. Biol Pharm Bull 19, 644-646, 1996.
  35. Petkov, V.D., Kehayov, R., Belcheva, S., Konstantinova, E., Petkov, V.V., Cetova, D., Markovska, V. Memory effects of standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701). Planta Med 59, 106-114, 1993.
  36. Lim, J.H., Wen, T.C., Matsuda, S., Tanaka, J., Maeda, N., Peng, H., Aburaya, J., Ishihara, K., Sakanaka, M. Protection of ischemic hippocampal neurons by ginsenoside Rb1, a main ingredient of ginseng root. Neurosci Res 28, 191-200, 1997.