Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Memory Enhancing and Neuroprotective Effects of Selected Ginsenosides

  • Sao Hai Ying (College of Medicinal Material, Jilin Agricultural University) ;
  • Zhang Jing (College of Medicinal Material, Jilin Agricultural University) ;
  • Yeo Soo Jeong (College of Pharmacy, Chungnam National University) ;
  • Myung Chang Seon (College of Pharmacy, Chungnam National University) ;
  • Kim Hyang Mi (College of Medicine, Dongguk University) ;
  • Kim Jong Moon (Central Research Institute, Iisung Pharmaceutical Co.) ;
  • Park Jeong Hill (College of Pharmacy, Seoul National University) ;
  • Cho Jung Sook (College of Medicine, Dongguk University) ;
  • Kang Jong Seong (College of Pharmacy, Chungnam National University)
  • Published : 2005.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

The effects of ginsenosides Rg$_3$(R) , Rg$_3$(S) and Rg$_5$/Rk$_1$ (a mixture of Rg$_5$ and Rk$_1$ 1:1, w/w), which are components isolated from processed Panax ginseng C.A. Meyer (Araliaceae), on memory dysfunction were examined in mice using a passive avoidance test. The ginsenosides Rg3(R), Rg3(S) or Rg$_5$/Rk$_1$, when orally administered for 4 days, significantly ameliorated the memory impairment induced by the single oral administration of ethanol. The memory impairment induced by the intraperitoneal injection of scopolamine was also significantly recovered by ginsenosides Rg3(S) and Rg$_5$/Rk$_1$. Among the three ginsenosides tested in this study, Rg$_5$/Rk$_1$ enhanced the memory function of mice most effectively in both the ethanol­and scopolamine-induced amnesia models. Moreover, the latency period of the Rg$_5$/Rk$_1$­treated mice was 1.2 times longer than that of the control (no amnesia) group in both models, implying that Rg$_5$/Rk$_1$ may also exert beneficial effects in the normal brain. We also evaluated the effects of these ginsenosides on the excitotoxic and oxidative stress-induced neuronal cell damage in primary cultured rat cortical cells. The excitotoxicity induced by glutamate or N­methyl-D-aspartate (NMDA) was dramatically inhibited by the three ginsenosides. Rg$_3$(S) and Rg$_5$/Rk$_1$ exhibited a more potent inhibition of excitotoxicity than did Rg$_3$(R). In contrast, these ginsenosides were all ineffective against the H$_2$O$_2$- or xanthine/xanthine oxidase-induced oxidative neuronal damage. Taken together, these results indicate that ginsenosides Rg$_3$(S) and Rg$_5$/Rk$_1$ significantly reversed the memory dysfunction induced by ethanol or scopolamine, and their neuroprotective actions against excitotoxicity may be attributed to their memory enhancing effects.

Keywords

References

  1. Attele, A. S., Wu, J. A., and Yuan, C. S., Ginseng pharmacology: multiple constituents and multiple actions. Biochem. Pharmacol., 58, 1685-1693 (1999) https://doi.org/10.1016/S0006-2952(99)00212-9
  2. Benishin, C. G., Actions of ginsenoside $Rb_1$ on choline uptake in central cholinergic nerve endings. Neurochem. International, 21, 1-5 (1992) https://doi.org/10.1016/0197-0186(92)90061-U
  3. Benishin, C. G., Lee, R., Wang, L. C., and Liu, H. J., Effects of ginsenoside $Rb_1$ on central cholinergic metabolism. Pharmacology, 42, 223-229 (1991) https://doi.org/10.1159/000138801
  4. Boileau, I., Assaad, J., Pihl, R. O., Benkelfat, C., Leyton, M., Diksic, M., Tremblay, R. E., and Dagher, A., Alcohol promotes dopamine release in the human nucleus accumbens. Synapse, 49, 226-231 (2003) https://doi.org/10.1002/syn.10226
  5. Brioni, J. D., McGaugh, J. L., and Izquierdo, I., Amnesia induced by short-term treatment with ethanol: attenuation by pretest oxotremorine. Pharmacol. Biochem. Behav., 33, 27- 29 (1989) https://doi.org/10.1016/0091-3057(89)90424-3
  6. Cho, J., Joo, N. E., Kong, J.-Y., Jeong, D.-Y., Lee, K. D., and Kang, B.-S., Inhibition of excitotoxic neuronal death by methanol extract of Acori graminei rhizoma in cultured rat cortical neurons. J. Ethnopharmacol., 73, 31-37 (2000) https://doi.org/10.1016/S0378-8741(00)00262-2
  7. Cho, J., Kang, J. S., Long, P. H., Jing, J., Back, Y., and Chung, K.-S., Antioxidant and memory enhancing effects of purple sweet potato anthocyanin and Cordyceps mushroom extract. Arch. Pharm. Res., 26, 821-825 (2003) https://doi.org/10.1007/BF02980027
  8. Cho, J., Kim, Y. H., Kong, J.-Y., Yang, C.-H., and Park, C.-G., Protection of cultured rat cortical neurons from excitotoxicity by asarone, a major essential oil component in the rhizomes of Acorus gramineus. Life Sci., 71, 591-599 (2002) https://doi.org/10.1016/S0024-3205(02)01729-0
  9. Cho, J., Kong, J.-Y., Jeong, D.-Y., Lee, K. D., Lee, D. U., and Kang, B.-S., NMDA receptor-mediated neuroprotection by essential oils from rhizomes of Acorus gramineus. Life Sci., 68, 1567-1573 (2001) https://doi.org/10.1016/S0024-3205(01)00944-4
  10. Cho, J. and Lee, H.-K., Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells. Eur. J. Pharmacol., 485, 105-110 (2004) https://doi.org/10.1016/j.ejphar.2003.11.064
  11. Choi, D. W. and Koh, J. Y., Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase. J. Neurosci. Meth., 20, 83-90 (1987) https://doi.org/10.1016/0165-0270(87)90041-0
  12. Coyle, J. T. and Puttfarcken, P., Oxidative stress, glutamate and neurodegenerative disorders. Science, 262, 689-695 (1993) https://doi.org/10.1126/science.7901908
  13. Dok-Go, H., Lee, K. H., Kim, H. J., Lee, E. H., Lee, J., Song, Y. S., Lee, Y.-H., Jin, C., Lee, Y. S., and Cho, J., Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res., 965, 130- 136 (2003) https://doi.org/10.1016/S0006-8993(02)04150-1
  14. Halliwell, B., Reactive oxygen species and the central nervous system. J. Neurochem., 59, 1609-1623 (1992) https://doi.org/10.1111/j.1471-4159.1992.tb10990.x
  15. Hayashi, M., Nakai, T., Bandoh, T., and Hoshi, K., Acute effect of simultaneous administration of tryptophan and ethanol on serotonin metabolites in the locus ceruleus in rats. Eur. J. Pharmacol., 462, 61-66 (2003) https://doi.org/10.1016/S0014-2999(03)01318-9
  16. Jin, S. H., Park. J. K., Nam. K. Y., Park. S. N., and Jung. N. P., Korean red ginseng saponins with low ratios of protopanaxadiol and protopanaxatriol saponin improve scopolamineinduced learning disability and spatial working memory in mice. J. Ethnopharmacol., 66, 123-129 (1999) https://doi.org/10.1016/S0378-8741(98)00190-1
  17. Jung, Y.-S., Kang, T.-S., Yoon, J.-H., Joe, B.-Y., Lim, H.-J., Seong, C.-M., Park, W.-K., Kong, J.-Y., Cho, J., and Park, N.- S., Synthesis and evaluation of 4-hydroxyphenylacetic acid amides and 4-hydroxycinnamamides as antioxidants. Bioorg. Med. Chem. Lett., 12, 2599-2602 (2002) https://doi.org/10.1016/S0960-894X(02)00479-1
  18. Kennedy, D. and Scholey, A., Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol. Biochem. Behav., 75, 687-700 (2003) https://doi.org/10.1016/S0091-3057(03)00126-6
  19. Kim, S., Ahn, K., Oh, T. H., and Nah, S.-Y., and Rhim, H., Inhibitory effects of ginsenosides on NMDA receptormediated signals in rat hippocampal neurons. Biochem. Biophys. Res. Commun., 296, 247-254 (2002) https://doi.org/10.1016/S0006-291X(02)00870-7
  20. Kim, Y. C., Kim, S. R., Markelonis, G. J., and Oh, T. H., Ginsenosides $Rb_1$ and $Rg_3$s protect cultured rat cortical cells from glutamate-induced neurodegeneration. J. Neurosci. Res., 53, 426-432 (1998) https://doi.org/10.1002/(SICI)1097-4547(19980815)53:4<426::AID-JNR4>3.0.CO;2-8
  21. Kopelman, M. D. and Corn, T. H., Cholinergic 'blockade' as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. Brain, 111, 1079-110 (1988) https://doi.org/10.1093/brain/111.5.1079
  22. Kwon, S. W., Han, S. B., Park, I. H., Kim, J. M., Park, M. K., and Park, J. H., Liquid chromatographic determination of less polar ginsenosides in processed ginseng. J. Chromatogr. A, 921, 335-339 (2001) https://doi.org/10.1016/S0021-9673(01)00869-X
  23. Lee, S. C., You, K. H., and Kim, E. B., The functional role of limbic system on memory: Behavioral and neurochemical alterations following acute administration of ethanol in rats. J. Pharm. Sci., 11, 1-10 (1995)
  24. Li, J. and Zhang, J., Inhibition of apoptosis by ginsenoside TEX>$Rg_1$ in cultured cortical neurons. Chin. Med. J., 110, 535-539 (1997)
  25. Liao, B., Newmark, H., and Zhou, R., Neuroprotective effects of ginseng total saponin and ginsenosides $Rb_1$ and TEX>$Rg_1$ on spinal cord neurons in vitro. Experiment. Neurol., 173, 224- 234 (2002) https://doi.org/10.1006/exnr.2001.7841
  26. Mook-Jung, I., Hong, H. -S., Boo, J. H., Lee, K. H., Yun, S. H., Cheong, M. Y., Joo, I., Huh, K., and Jung, M. W., Ginsenoside$Rb_1$ and $Rg_1$ improve spatial learning and increase hippocampal synaptophysin level in mice. J. Neurosci. Res., 63, 509-515 (2001) https://doi.org/10.1002/jnr.1045
  27. Nevo, I. and Hamon, M., Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism. Neurochem. International, 26, 305-36 (1995) https://doi.org/10.1016/0197-0186(94)00139-L
  28. Nishiyama, N., Cho, S. I., Kitagawa, I., and Saito, H., Malonylginsenoside $Rb_1$ potentiates nerve growth factor (NGF)- induced neurite outgrowth of cultured chick embryonic dorsal root ganglia. Biol. Pharmacol. Bull., 17, 509-513 (1994) https://doi.org/10.1248/bpb.17.509
  29. Okaichi, H., Oshima, Y., and Jarrard, L. E., Scopolamine impairs both working and reference memory in rats: a replication and extension. Pharmacol. Biochem. Behav., 34, 599-602 (1989) https://doi.org/10.1016/0091-3057(89)90565-0
  30. Petkov, V. D. and Mosharrof, A. H., Effects of standardized ginseng extract on learning, memory and physical capabilities. Am. J. Chin. Med., 15, 19-29 (1987) https://doi.org/10.1142/S0192415X87000047
  31. Pitsikas, N., Rigamonti, A. E., Cella, S. G., Locatelli, V., Sala, M., and Muller, E. E., Effects of molsidomine on scopolamineinduced amnesia and hypermotility in the rat. Eur. J. Pharmacol., 426, 193-200 (2001) https://doi.org/10.1016/S0014-2999(01)01164-5
  32. Raghavendra, V. and Kulkarni, S. K., Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks. Free Rad. Biol. Med., 30, 595-602 (2001) https://doi.org/10.1016/S0891-5849(00)00447-0
  33. Saito, H., Effects of ginsenoside $Rb_1$ and ginsenoside $Rg_1$ on learning and memory. In Shibata, S., Ohtsuka, Y. and Saito, H. (Eds.), Recent Advances in Ginseng Study. Hirokawa Publishing, Tokyo, p.99 (1990)
  34. Sauer, D. and Fagg, G. E., Excitatory amino acids, excitotoxicity and neurodegenerative disorders. In Krogsgaard-Larsen, P., Hansen, J. J. (Eds.), Excitatory Amino Acid Receptors. Ellis Horwood, New York, NY, pp. 13-33 (1992)
  35. Takaku, T., Kameda, K., Matsuura, Y., Sekiya, K., and Okuda, H., Studies on insulin-like substances in Korean red ginseng. Planta Med., 56, 27-30 (1990) https://doi.org/10.1055/s-2006-960877
  36. Tohda, C., Matsumoto, N., Zou, K., Meselhy, M. R., and Komatsu, K., $A^{\beta(25-35)}$-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by $M_1$, a metabolite of protopanaxadiol-type saponins. Neuropsychopharmacol., 29, 860-868 (2004) https://doi.org/10.1038/sj.npp.1300388
  37. Tracy, H. A. Jr., Wayner, M. J., and Armstrong, D. L., Losartan improves the performance of ethanol-intoxicated rats in an eight-arm radial maze. Alcohol, 14, 511-517 (1997) https://doi.org/10.1016/S0741-8329(97)00041-4
  38. Wallenstein, G. V. and Vago, D. R., Intrahippocampal scopolamine impairs both acquisition and consolidation of contextual fear conditioning. Neurobiol. Learn. Mem., 75, 245- 252 (2001) https://doi.org/10.1006/nlme.2001.4005
  39. Yamaguchi, Y., Haruta, K., and Kobayashi, H., Effects of ginsenosides on impaired performance induced in the rat by scopolamine in a radial-arm maze. Psychoneuroendocrinol., 20, 645-653 (1995) https://doi.org/10.1016/0306-4530(95)00008-C
  40. Yamaguchi, Y., Higashi, M., and Kobayashi, H., Effects of ginsenosides on impaired performance caused by scopolamine in rats. Eur. J. Pharmacol., 312, 149-151 (1996) https://doi.org/10.1016/0014-2999(96)00597-3
  41. Zhang, J. T., Qu, Z. W., Liu, Y., and Deng, H. L., Preliminary study on antiamnesic mechanism of ginsenosides $Rg_1$ and $Rb_1$, Chin. Med. J., 103, 932-938 (1990)
  42. Zhong, Y. M., Nishijo, H., Uwano, T., Tamura, R., Kawanishi, K., and Ono, T., Red ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats. Physiol. Behav., 69, 511-525 (2000) https://doi.org/10.1016/S0031-9384(00)00206-7