Ginsenoside Rg3 from Red Ginseng Prevents Damage of Neuronal Cells through the Phosphorylation of the Cell Survival Protein Akt

  • Joo, Seong-Soo (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Won, Tae-Joon (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Lee, Yong-Jin (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Hwang, Kwang-Woo (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Lee, Seon-Gu (Department of Pathology, College of Oriental Medicine, Sangji University) ;
  • Yoo, Yeong-Min (Department of Pathology, College of Oriental Medicine, Sangji University) ;
  • Lee, Do-Ik (Department of Immunology, College of Pharmacy, Chung-Ang University)
  • Published : 2006.04.30

Abstract

Neuronal cell death significantly contributes to neuronal loss in neurological injury and disease. Typically, neuronal loss or destruction upon exposure to neurotoxins, oxidative stress, or DNA damage causes neurodegenerative diseases such as Alzheimer's disease. In this study, we attempted to determine whether ginsenoside Rg3 from red ginseng has a neuroprotective effect via an anti-apoptotic role induced by S-nitroso-N-acetylpenicillamine (SNAP) at the molecular level. We also investigated the antioxidant effect of Rg3 using a metal-catalyzed reaction with $Cu^{2+}/H_2O_2$. Our results showed that Rg3 ($40-100\;{\mu}g/mL$) protected SK-N-MC neuroblastoma cells under cytotoxic conditions and effectively protected DNA from fragmentation. In the signal pathway, caspase-3, and poly (ADP-ribose) polymerase (PARP) were kept at an inactivated status when pretreated with Rg3 in all ranges. In particular, the important upstream p-Akt signal pathway was increased in a dose-dependent manner, which indicates that Rg3 may contribute to cell survival. We also found that oxidative stress can be mitigated by Rg3. Therefore, we have concluded that Rg3 plays a certain role in neurodegenerative pathogenesis via an anti apoptotic, antioxidative effect.

Keywords

References

  1. Carson DA, Rebeiro JM. Apoptosis and disease. Lancet 341: 1251-1254 (1993) https://doi.org/10.1016/0140-6736(93)91154-E
  2. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456-1462 (1995) https://doi.org/10.1126/science.7878464
  3. Takuma K, Yan SS, Stem DM, Yamada K. Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease. J. Pharmacol. Sci. 97: 312-316 (2005) https://doi.org/10.1254/jphs.CPJ04006X
  4. Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 5: S18-S25 (2004) https://doi.org/10.1038/ni0104-18
  5. Dickson DW. Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? J. Clin. Invest. 114:23-27 (2004) https://doi.org/10.1172/JCI22317
  6. Stadelmann C, Bruck W, Bancher C, Jellinger K, Lassmann H. Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J. Neuropath. Exp. Neur. 57: 456464 (1998) https://doi.org/10.1097/00005072-199805000-00009
  7. Glabe C. Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. J. Mol. Neurosci. 17: 137-145 (2001) https://doi.org/10.1385/JMN:17:2:137
  8. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Tripletransgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39: 409-421 (2003) https://doi.org/10.1016/S0896-6273(03)00434-3
  9. Yao R, Cooper GM. Requirement for phosphatidylinositol-3kinase in the prevention of apoptosis by nerve growth factor. Science 267: 2003-2006 (1995) https://doi.org/10.1126/science.7701324
  10. Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three akts. Gene Dev. 13: 2905-2927 (1999) https://doi.org/10.1101/gad.13.22.2905
  11. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW. Apoptosis is induced by -amy1oid in cultured central nervous system neurons. P. Natl. Acad. Sci. USA 90: 7951-7955 (1993)
  12. Troy CM, Rabacchi SA, Friedman WJ, Frappier TF, Brown K, Shelanski ML. Caspase-2 mediates neuronal cell death induced by beta-amyloid. J. Neurosci. 209: 1386-1392 (2000)
  13. Chen XC, Zhu YG, Zhu LA, Huang C, Chen Y, Chen LM, Fang F, Zhou YC, Zhao CH. Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress. Eur. J. Pharmacol. 473: 1-7 (2003) https://doi.org/10.1016/S0014-2999(03)01945-9
  14. Liao B, Newmark H, Zhou R. Neuroprotective effects of ginseng total saponin and ginsenosides RbI and Rgl on spinal cord neurons in vitro. Exp. Neurol. 173: 224-234 (2002) https://doi.org/10.1006/exnr.2001.7841
  15. Ko SK, Lee HL, Hong JK, Kang SA, Sohn UD, Im BO, Han ST, Yang BW, Chung SH, Lee BY. Changes of ginsenoside composition in ginseng extract by vinegar process. Food Sci. Biotechnol. 14: 509-513 (2005)
  16. Seog HM, Jung CH, Kim YS, Park HS. Phenolic acids and antioxidant activities of wild ginseng. Food Sci. Biotechnol. 14: 371374 (2005)
  17. Benishin CG. Actions of ginsenoside RbI on choline uptake in central cholinergic metabolism. Phamacology 42: 223-229 (1992)
  18. Kim SH, Kim TH, Ahn KS, Park WK, Nah SY, Rhim HW. Ginsenoside Rg3 antagonizes NMDA receptors through a glycine modulatory site in rat cultured hippocampal neurons. Biochem. Bioph. Res. Co. 323: 416-424 (2004) https://doi.org/10.1016/j.bbrc.2004.08.106
  19. Joo SS, Won TJ, Lee DI. Reciprocal activity of ginsenosides in the production of pro inflammatory repertoire, and their potential roles in neuroprotection in vitro. Planta Med. 71: 476-481 (2005) https://doi.org/10.1055/s-2005-864145
  20. Joo SS, Lee DI. Potential effects of microglial activation induced by ginsenoside Rg3 in rat primary culture: enhancement of type A macrophage scavenger receptor expression. Arch. Pharm. Res. 28: 1164-1169 (2005) https://doi.org/10.1007/BF02972981
  21. Yoo Y.M, Vim SV, Kim SS, Jang BY, Lea HZ, Hwang GC, Kim JW, Kim SA, Lee HJ, Kim CJ, Chung JR, Leem KH. Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells. J. Pineal. Res. 33: 146-150 (2002) https://doi.org/10.1034/j.1600-079X.2002.02899.x
  22. Banati RB, Gehrmann J, Schubert P, Kreutzberg Gw. Cytotoxicity of microglia. Glia 7: 111-118 (1996) https://doi.org/10.1002/glia.440070117
  23. Giulian D. Ameboid microglia as effectors of inflammation in the central nervous system. J. Neurosci. Res. 18: 155-171 (1987) https://doi.org/10.1002/jnr.490180123