Archives of Pharmacal Research

, Volume 33, Issue 10, pp 1655–1664 | Cite as

Leaf and stem of Vitis amurensis and its active components protect against amyloid β protein (25–35)-induced neurotoxicity

  • Ha Yeon Jeong
  • Joo Youn Kim
  • Hong Kyu Lee
  • Do Thi Ha
  • Kyung-Sik Song
  • KiHwan BaeEmail author
  • Yeon Hee SeongEmail author
Research Articles Drug Discovery and Development


This study investigated a methanol extract from the leaf and stem of Vitis amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid β protein (Aβ) (25–35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 μM Aβ (25–35) for 36 h induced neuronal apoptotic death. At concentrations of 1–10 μg/mL, V. amurensis inhibited neuronal death, the elevation of intracellular calcium ([Ca2+]i) and the generation of reactive oxygen species (ROS), all of which were induced by Aβ (25–35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 16 nmol Aβ (25–35) was inhibited by chronic treatment with V. amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G, r-2-viniferin and trans-ɛ-viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca2+]i and the generation of ROS induced by Aβ (25–35) in cultured rat cortical neurons. These results suggest that the neuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the antidementia effect of V. amurensis is due to its neuroprotective effect against Aβ (25–35)-induced neurotoxicity and that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer’s disease.

Key words

Vitis amurensis Amurensin G r-2-Viniferin trans-ɛ-Viniferin Amyloid β protein Neuroprotection Memory impairment 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ban, J. Y. and Seong, Y. H., Blockade of 5-HT3 receptor with MDL72222 and Y25130 reduces β-amyloid protein (25–35)-induced neurotoxicity in cultured rat cortical neurons. Eur. J. Pharmacol., 520, 12–21 (2005).CrossRefGoogle Scholar
  2. Ban, J. Y., Jeon, S. Y., Bae, K., Song, K. S., and Seong, Y. H., Catechin and epicatechin from Smilacis chinae rhizome protect cultured rat cortical neurons against amyloid beta protein (25–35)-induced neurotoxicity through inhibition of cytosolic calcium elevation. Life Sci., 79, 2251–2259 (2006).CrossRefPubMedGoogle Scholar
  3. Butterfield, D. A. and Lauderback, C. M., Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic. Biol. Med., 32, 1050–1060 (2002).CrossRefPubMedGoogle Scholar
  4. Cho, S. O., Ban, J. Y., Kim, J. Y., Jeong, H. Y., Lee, I. S., Song, K. S., Bae, K. H., and Seong, Y. H., Aralia cordata protects against amyloid beta protein (25–35)-induced neurotoxicity in cultured neurons and has antidementia activities. J. Pharmacol. Sci., 111, 22–32 (2009).CrossRefPubMedGoogle Scholar
  5. Demuro, A., Parker, I., and Stutzmann, G. E., Calcium signaling and amyloid toxicity in Alzheimer disease. J. Biol. Chem., 285, 12463–12468 (2010).CrossRefPubMedGoogle Scholar
  6. Ekinci, F. J., Linsley, M. D., and Shea, T. B., Beta-amyloidinduced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation. Brain Res. Mol. Brain Res., 76, 389–395 (2000).CrossRefPubMedGoogle Scholar
  7. Ellman, G. L., Courtney, K. D., Andres, V., and Featherstone, R. M., A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 7, 88–95 (1961).CrossRefPubMedGoogle Scholar
  8. Francis, P. T., Palmer, A. M., Snape, M., and Wilcock, G. K., The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J. Neurol. Neurosurg. Psychiatr., 66, 137–147 (1999).CrossRefPubMedGoogle Scholar
  9. Gasparini, L., Ongini, E., and Wenk, G., Non-steroidal antiinflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action. J. Neurochem., 91, 521–536 (2004).CrossRefPubMedGoogle Scholar
  10. Gitter, B. D., Cox, L. M., Rydel, R. E., and May, P. C., Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proc. Natl. Acad. Sci. U.S.A., 92, 10738–10741 (1995).CrossRefPubMedGoogle Scholar
  11. Gray, C. W. and Patel, A. J., Neurodegeneration mediated by glutamate and beta-amyloid peptide: a comparison and possible interaction. Brain Res., 691, 169–179 (1995).CrossRefPubMedGoogle Scholar
  12. Ha, D. T., Chen, Q. C., Hung, T. M., Youn, U. J., Ngoc, T. M., Thuong, P. T., Kim, H. J., Seong, Y. H., Min, B. S., and Bae, K. H., Stilbenes and loigostilbenes from leaf and stem of Vitis amurensis and their cytotoxic activity. Arch. Pharm. Res., 32, 177–183 (2009a).CrossRefGoogle Scholar
  13. Ha, D. T., Kim, H., Thuong, P. T., Ngoc, T. M., Lee, K., Hung, N. D., and Bae, K. H., Antioxidant and lipoxygenase inhibitory activity of oligostilbenes from the leaf and stem of Vitis amurensis. J. Ethnopharmacol., 125, 304–309 (2009b).CrossRefGoogle Scholar
  14. Hardy, J. and Selkoe, D. J., The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297, 353–356 (2002).CrossRefPubMedGoogle Scholar
  15. Heneka, M. T. and O’Banion, M. K., Inflammatory processes in Alzheimer’s disease. J. Neuroimmunol., 184, 69–91 (2007).CrossRefPubMedGoogle Scholar
  16. Holscher, C., Gengler, S., Gault, V. A., Harriott, P., and Mallot, H. A., Soluble beta-amyloid [25–35] reversibly impairs hippocampal synaptic plasticity and spatial learning. Eur. J. Pharmacol., 561, 85–90 (2007).CrossRefPubMedGoogle Scholar
  17. Huang, H. J., Liang, K. C., Chen, C. P., Chen, C. M., and Hsieh-Li, H. M., Intrahippocampal administration of A beta (1–40) impairs spatial learning and memory in hyperglycemic mice. Neurobiol. Learn. Mem., 87, 483–494 (2007).CrossRefPubMedGoogle Scholar
  18. Huang, K. S. and Lin, M., Oligostibenes from the roots of Vitis amurensis. J. Asian Nat. Prod. Res., 2, 21–28 (1999).CrossRefPubMedGoogle Scholar
  19. Huang, K. S., Lin, M., Yu, L. N., and Kong, M., Four novel oligostibenes from the roots of Vitis amurensis. Tetrahedron, 56, 1321–1329 (2000).CrossRefGoogle Scholar
  20. Huang, K. S., Lin, M., and Cheng, G. F., Anti-inflammatory tetramers of resveratrol from the roots of Vitis amurensis and the conformations of the seven-membered ring in some oligostilbenes. Phytochemistry, 58, 357–362 (2001).CrossRefPubMedGoogle Scholar
  21. Jakab, M., Lach, S., Bacova, Z., Langeluddecke, C., Strbak, V., Schmidt, S., Lglseder, E., Paulmichl, M., Geibel, J., and Ritter, M., Resveratrol inhibits electrical activity and insulin release from insulinoma cells by block of voltagegated Ca2+ Channels and swelling-dependent Clcurrents. Cell. Physiol. Biochem., 22, 567–578 (2008).CrossRefPubMedGoogle Scholar
  22. Jang, M. H., Piao, X. L., Kim, H. Y., Cho, E. J., Baek, S. H., Kwon, S. W., and Park, J. H., Resveratrol oligomers from Vitis amurensis attenuate â-amyloid-induced oxidative stress in PC12 cells. Biol. Pharm. Bull., 30, 1130–1134 (2007).CrossRefPubMedGoogle Scholar
  23. Kontush, A., Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer’s disease. Free Radic. Biol. Med., 31, 1120–1131 (2001).CrossRefPubMedGoogle Scholar
  24. Korhammer, S., Reniero, F., and Mattivi, F., An oligostilbene from Vitis roots. Phytochemistry, 38, 1501–1504 (1995).CrossRefGoogle Scholar
  25. Lee, B. Y., Ban, J. Y., and Seong, Y. H., Chronic stimulation of GABAA receptor with muscimol reduces amyloid beta protein (25–35)-induced neurotoxicity in cultured rat cortical cells. Neurosci. Res., 52, 347–356 (2005).CrossRefPubMedGoogle Scholar
  26. Lee, E. O., Lee, H. J., Hwang, H. S., Ahn, K. S., Chae, C., Kang, K. S., Lu, J., and Kim, S. H., Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis, 27, 2059–2069 (2006).CrossRefPubMedGoogle Scholar
  27. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J., Protein measurements with the Folin phenol reagent. J. Biol. Chem., 193, 265–275 (1951).PubMedGoogle Scholar
  28. Mattson, M. P. and Chan, S. L., Calcium orchestrates apoptosis. Nat. Cell Biol., 5, 1041–1043 (2003).CrossRefPubMedGoogle Scholar
  29. Maurice, T., Lockhart, B. P., and Privat, A., Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res., 706, 181–193 (1996).CrossRefPubMedGoogle Scholar
  30. McDonald, D. R., Brunden, K. R., and Landreth, G. E., Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J. Neurosci., 17, 2284–2294 (1997).PubMedGoogle Scholar
  31. Nassiri-Asl, M. and Hosseinzadeh, H., Review of the phar macological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother. Res., 23, 1197–1204 (2009).CrossRefPubMedGoogle Scholar
  32. Petersen, R. B., Nunomura, A., Lee, H. G., Casadesus, G., Perry, G., Smith, M. A., and Zhu, X., Signal transduction cascades associated with oxidative stress in Alzheimer’s disease. J. Alzheimers Dis., 11, 143–152 (2007).PubMedGoogle Scholar
  33. Pike, C. J., Walencewicz-Wasserman, A. J., Kosmoski, J., Cribbs, D. H., Glabe, C. G., and Cotman, C. W., Structureactivity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J. Neurochem., 64, 253–265 (1995).CrossRefPubMedGoogle Scholar
  34. Richardson, J. S., Zhou, Y., and Kumar, U., Free radicals in the neurotoxic actions of beta-amyloid. Ann. N. Y. Acad. Sci., 777, 362–367 (1996).CrossRefPubMedGoogle Scholar
  35. Ruan, C. J., Si, J. Y., Zhang, L., Chen, D. H., Du, G. H., and Su, L., Protective effect of stilbenes containing extractfraction from Cajanus cajan L. on A beta (25–35)-induced cognitive deficits in mice. Neurosci. Lett., 467, 159–163 (2009).CrossRefPubMedGoogle Scholar
  36. Sano, M., Ernesto, C., Thomas, R. G., Klauber, M. R., Schafer, K., Grundman, M., Woodbur, P., Growdon, J., Cotman, C. W., Pfeiffer, E., Schneider, L. S., and Thal, L. J., A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N. Engl. J. Med., 336, 1216–1222 (1997).CrossRefPubMedGoogle Scholar
  37. Smith, M. A., Richey Harris, P. L., Sayre, L. M., Beckman, J. S., and Perry, G., Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci., 17, 2653–2657 (1997).PubMedGoogle Scholar
  38. Solntseva, E. I., Bukanova, J. V., Marchenko, E., and Skrebitsky, V. G., Donepezil is a strong antagonist of voltagegated calcium and potassium channels in molluscan neurons. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 144, 319–326 (2007).CrossRefPubMedGoogle Scholar
  39. Stepanichev, M. Y., Moiseeva, Y. V., Lazareva, N. A., Onufriev, M. V., and Gulyaeva, N. V., Single intracerebroventricular administration of amyloid-beta (25–35) peptide induces impairment in short-term rather than longterm memory in rats. Brain Res. Bull., 61, 197–205 (2003).CrossRefPubMedGoogle Scholar
  40. Thomas, P., Wang, Y. J., Zhong, J. H., Kosaraju, S., O’Callaghan, N. J., Zhou, X. F., and Fenech, M., Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzhimer’s disease. Mutat. Res., 661, 25–34 (2009).PubMedGoogle Scholar
  41. 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 M1, A metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology, 29, 860–868 (2004).CrossRefPubMedGoogle Scholar
  42. Ueda, K., Shinohara, S., Yagami, T., Asakura, K., and Kawasaki, K., Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals. J. Neurochem., 68, 265–271 (1997).CrossRefPubMedGoogle Scholar
  43. Van Dam, D. and De Deyn, P. P., Drug discovery in dementia: the role of rodent models. Nat. Rev. Drug Discov., 5, 956–970 (2006).CrossRefPubMedGoogle Scholar
  44. Van Marum, R. J., Current and future therapy in Alzheimer’s disease. Fundam. Clin. Pharmacol., 22, 265–274 (2008).CrossRefPubMedGoogle Scholar
  45. Wang, J., Ho, L., Zhao, W., Ono, K., Rosensweig, C., Chen, L., Humala, N., Teplow, D. B., and Pasinetti, G. M., Grapederived polyphenolics prevent A beta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J. Neurosci., 28, 6388–6392 (2008).CrossRefPubMedGoogle Scholar
  46. Wenk, G. L., Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J. Clin. Psychiatry, 67 Suppl 3, 3–7 (2006).Google Scholar
  47. Yamada, K., Tanaka, T., Han, D., Senzaki, K., Kameyama, T., and Nabeshima, T., Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1–42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. Eur. J. Neurosci., 11, 83–90 (1999).CrossRefPubMedGoogle Scholar
  48. Yim, N. H., Ha, D. T., Trung, T. N., Kim, J. P., Lee, S. M., Na, M. K., Jung, H. J., Kim, H. S., Kim, Y. H., and Bae, K. H., The antimicrobial activity of compounds from the leaf and stem of Vitis amurensis against two oral pathogens. Bioorg. Med. Chem. Lett., 20, 1165–1168 (2010).CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2010

Authors and Affiliations

  • Ha Yeon Jeong
    • 1
  • Joo Youn Kim
    • 1
  • Hong Kyu Lee
    • 1
  • Do Thi Ha
    • 2
  • Kyung-Sik Song
    • 3
  • KiHwan Bae
    • 2
    Email author
  • Yeon Hee Seong
    • 1
    Email author
  1. 1.College of Veterinary MedicineChungbuk National UniversityCheongjuKorea
  2. 2.College of PharmacyChungnam National UniversityTaejonKorea
  3. 3.College of Agriculture and Life-SciencesKyungpook National UniversityDaeguKorea

Personalised recommendations