DOI QR코드

DOI QR Code

Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer's Disease

  • Kim, Hyeon-Joong (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Shin, Eun-Joo (Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University) ;
  • Lee, Byung-Hwan (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Choi, Sun-Hye (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Jung, Seok-Won (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Cho, Ik-Hyun (Department of Convergence Medical Science, Brain Korea 21 Plus Program, and Institute of Oriental Medicine) ;
  • Hwang, Sung-Hee (Department of Pharmaceutical Engineering, Sangji University) ;
  • Kim, Joon Yong (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Han, Jung-Soo (Department of Biological Sciences, Konkuk University) ;
  • Chung, ChiHye (Department of Biological Sciences, Konkuk University) ;
  • Jang, Choon-Gon (Department of Pharmacology, College of Pharmacy, Sungkyunkwan University) ;
  • Rhim, Hyewon (Center for Neuroscience, Korea Institute of Science and Technology Seoul) ;
  • Kim, Hyoung-Chun (Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University) ;
  • Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
  • Received : 2015.05.04
  • Accepted : 2015.06.29
  • Published : 2015.09.30

Abstract

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced $[Ca^{2+}]_i $ transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated $[Ca^{2+}]_i $ transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 1 2 weeks) also significantly attenuated amyloid-${\beta}$ protein ($A{\beta}$)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to $A{\beta}$ and could be utilized for AD prevention or therapy.

Acknowledgement

Supported by : Ministry of Education, Science, and Technology

References

  1. Alzheimer, A. (1907). Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Zeitschrife Psychiatr. 64, 146-148.
  2. Bales, K.R., Tzavara, E.T., Wu, S., Wade, M.R., Bymaster, F.P., Paul, S.M., and Nomikos, G.G. (2006). Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody. J. Clin. Invest. 116, 825-832. https://doi.org/10.1172/JCI27120
  3. Bartus, R.T., Dean, R.L., Beer, B., and Lippa, A.S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408-414. https://doi.org/10.1126/science.7046051
  4. Braak, H., Braak, E., Grundke-Iqbal, I., and Iqbal, K. (1986). Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65, 351-355. https://doi.org/10.1016/0304-3940(86)90288-0
  5. Castilla-Ortega, E., Sanchez-Lopez, J., Hoyo-Becerra, C., Matas-Rico, E., Zambrana-Infantes, E., Chun, J., De Fonseca, F.R., Pedraza, C., Estivill-Torrus, G., and Santin, L.J. (2010). Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor. Neurobiol. Learn. Mem. 94, 73-82. https://doi.org/10.1016/j.nlm.2010.04.003
  6. Castilla-Ortega, E., Hoyo-Becerra, C., Pedraza, C., Chun, J., Rodriguez De Fonseca, F., Estivill-Torrus, G., and Santin, L.J. (2011). Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA1 receptor knockout mice. PLoS One 6, e25522. https://doi.org/10.1371/journal.pone.0025522
  7. Castilla-Ortega, E., Pedraza, C., Chun, J., de Fonseca, F.R., Estivill-Torrus, G., and Santin, L.J. (2012). Hippocampal c-Fos activation in normal and LPA-null mice after two object recognition tasks with different memory demands. Behav. Brain Res. 232, 400-405. https://doi.org/10.1016/j.bbr.2012.04.018
  8. Chao, L.P., and Wolfgram, F. (1972). Spectrophotometric assay for choline acetyltransferase. Anal. Biochem. 46, 114-118. https://doi.org/10.1016/0003-2697(72)90401-0
  9. Choi, S.H., Jung, S.W., Kim, H.S., Kim, H.J., Lee B.H., Kim, J.Y., Kim J.H., Hwang, S.H., Rhim, H., Kim, HC., et al. (2015a). A brief method for the preparation of gintonin-enriched fraction from ginseng. J. Ginseng Res. doi:10.1016/j.jgr.2015.05.002 (in press). https://doi.org/10.1016/j.jgr.2015.05.002
  10. Choi, S.H., Hong, M.K., Kim, H.J., Ryoo, N., Rhim, H., Nah, S.Y., and Kang, L.W. (2015b). Crystal structure of ginseng major latex-like protein 151 and its proposed lysophosphatidic acidbinding mechanism. Acta Crystallogr. D Biol. Crystallogr. 71, 1039-1050. https://doi.org/10.1107/S139900471500259X
  11. Colom, L.V., Castaneda, M.T., Hernandez, S., Perry, G., Jaime, S., Touhami, A. (2011). Intrahippocampal amyloid-${\beta}$ (1-40) injections injure medial septal neurons in rats. Curr. Alzheimer Res. 8, 832-840. https://doi.org/10.2174/156720511798192763
  12. Cui, H.L., and Qiao, J.T. (2006). Promotive action of lysophosphatidic acid on proliferation of rat embryonic neural stem cells and their differentiation to cholinergic neurons in vitro. Sheng Li Xue Bao 58, 547-555.
  13. Dash, P.K., Orsi, S.A., Moody, M., and Moore, A.N. (2004). A role for hippocampal Rho-ROCK pathway in long-term spatial memory. Biochem. Biophys. Res. Commun. 322, 893-898. https://doi.org/10.1016/j.bbrc.2004.08.004
  14. Davie, B.J., Christopoulos, A., and Scammells, P.J. (2013). Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. ACS Chem. Neurosci. 4, 1026-1048. https://doi.org/10.1021/cn400086m
  15. Dubin, A.E., Bahnson, T., Weiner, J.A., Fukushima, N., and Chun, J. (1999). Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and L-glutamate in early, presumptive cortical neuroblasts. J. Neurosci. 19, 1371-1381.
  16. Van Der Flier, W.M., Van Den Heuvel, D.M.J., Weverling-Rijnsburger, A.W.E., Spilt, A., Bollen, E.L.E.M., Westendorp, R.G.J., Middelkoop, H.A.M., and Van Buchem, M.A. (2002). Cognitive decline in AD and mild cognitive impairment is associated with global brain damage. Neurology 59, 874-879. https://doi.org/10.1212/WNL.59.6.874
  17. Hasebe, N., Fujita, Y., Ueno, M., Yoshimura, K., Fujino, Y., and Yamashita, T. (2013). Soluble ${\beta}$-amyloid Precursor Protein Alpha binds to p75 neurotrophin receptor to promote neurite outgrowth. PLoS One 8, e82321. https://doi.org/10.1371/journal.pone.0082321
  18. Hecht, J.H., Weiner, J.A., Post, S.R., and Chun, J. (1996). Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135, 1071-1083. https://doi.org/10.1083/jcb.135.4.1071
  19. Heo, J.H., Lee, S.T., Chu, K., Oh, M.J., Park, H.J., Shim, J.Y., and Kim, M. (2008). An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. Eur. J. Neurol. 15, 865-868. https://doi.org/10.1111/j.1468-1331.2008.02157.x
  20. Hooijmans, C.R., Rutters, F., Dederen, P.J., Gambarota, G., Veltien, A., van Groen, T., Broersen, L.M., Lutjohann, D., Heerschap, A., Tanila, H., et al. (2007). Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol. Dis. 28, 16-29. https://doi.org/10.1016/j.nbd.2007.06.007
  21. Hwang, S.H., Shin, T.J., Choi, S.H., Cho, H.J., Lee, B.H., Pyo, M.K., Lee, J.H., Kang, J., Kim, H.J., Park, C.W., et al. (2012a). Gintonin, newly identified compounds from ginseng, is novel lysophosphatidic acids-protein complexes and activates G protein-coupled lysophosphatidic acid receptors with high affinity. Mol. Cells 33, 151-162. https://doi.org/10.1007/s10059-012-2216-z
  22. Hwang, S.H., Shin, E.J., Shin, T.J., Lee, B.H., Choi, S.H., Kang, J., Kim, H.J., Kwon, S.H., Jang, C.G., Lee, J.H., et al. (2012b). Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates alzheimer's disease-related neuropathies: Involvement of non-amyloidogenic processing. J. Alzheimer's Dis. 31, 207-223.
  23. Hwang, S.H., Lee, B.H., Choi, S.H., Kim, H.J., Jung, S.W., Kim, H.S., Shin, H.C., Park, H.J., Park, K.H., Lee, M.K., et al. (2015). Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, stimulates neurotransmitter release. Neurosci. Lett. 584, 356-361. https://doi.org/10.1016/j.neulet.2014.11.007
  24. Jaffar, S., Counts, S.E., Ma, S.Y., Dadko, E., Gordon, M.N., Morgan, D., and Mufson, E.J. (2001) Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway. Exp. Neurol. 170, 227-243. https://doi.org/10.1006/exnr.2001.7710
  25. Jin, C.H., Shin, E.J., Park, J.B., Jang, C.G., Li, Z., Kim, M.S., Koo, K.H., Yoon, H.J., Park, S.-J., Choi, W.-C., et al. (2009). Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment. J. Neurosci. Res. 87, 3658-3670. https://doi.org/10.1002/jnr.22159
  26. Jung, B.D., Shin, E.J., Nguyen, X.K.T., Jin, C.H., Bach, J.H., Park, S.J., Nah, S.Y., Wie, M.B., Bing, G., and Kim, H.C. (2010). Potentiation of methamphetamine neurotoxicity by intrastriatal lipopolysaccharide administration. Neurochem. Int. 56, 229-244. https://doi.org/10.1016/j.neuint.2009.10.005
  27. Kennedy, D.O., and Scholey, A.B. (2003). Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol. Biochem. Behav. 75, 687-700. https://doi.org/10.1016/S0091-3057(03)00126-6
  28. Kim, J.H., Choi, S., Jung, J.E., Roh, E.J., and Kim, H.J. (2006). Capacitative Ca2+ entry is involved in regulating soluble amyloid precursor protein (sAPPalpha) release mediated by muscarinic acetylcholine receptor activation in neuroblastoma SH-SY5Y cells. J. Neurochem. 97, 245-254. https://doi.org/10.1111/j.1471-4159.2006.03734.x
  29. Kim, B.-W., Yang, S., Lee, C.H., and Son, H. (2011). A critical time window for the survival of neural progenitor cells by HDAC inhibitors in the hippocampus. Mol. Cells 31, 159-164. https://doi.org/10.1007/s10059-011-0019-5
  30. Kim, E.J., Jung, I.H., Van Le, T.K., Jeong, J.J., Kim, N.J., and Kim, D.H. (2013). Ginsenosides Rg5 and Rh3 protect scopolamineinduced memory deficits in mice. J. Ethnopharmacol. 146, 294-299. https://doi.org/10.1016/j.jep.2012.12.047
  31. Lee, S.T., Chu, K., Sim, J.Y., Heo, J.H., and Kim, M. (2008). Panax ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 22, 222-226. https://doi.org/10.1097/WAD.0b013e31816c92e6
  32. Liu, J.X., Cong, W.H., Xu, L., and Wang, J.N. (2004). Effect of combination of extracts of ginseng and ginkgo biloba on acetylcholine in amyloid beta-protein-treated rats determined by an improved HPLC. Acta Pharmacol. Sin. 25, 1118-1123.
  33. Maurice, T., Lockhart, B.P., and Privat, A. (1996). Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res. 706, 181-193. https://doi.org/10.1016/0006-8993(95)01032-7
  34. Pakaski, M., and Kalman, J. (2008). Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease. Neurochem. Int. 53, 103-111. https://doi.org/10.1016/j.neuint.2008.06.005
  35. Park, H., Kim, S., Rhee, J., Kim, H.J., Han, J.S., Nah, S.Y., and Chung, C. (2015). Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. J. Neurophysiol. 113, 1493-1500. https://doi.org/10.1152/jn.00667.2014
  36. Pedraza, C., Sanchez-Lopez, J., Castilla-Ortega, E., Rosell-Valle, C., Zambrana-Infantes, E., Garcia-Fernandez, M., Rodriguez de Fonseca, F., Chun, J., Santin, L.J., and Estivill-Torrus, G. (2014). Fear extinction and acute stress reactivity reveal a role of LPA(1) receptor in regulating emotional-like behaviors. Brain Struct. Funct. 219, 1659-1672. https://doi.org/10.1007/s00429-013-0592-9
  37. Perez, S.E., Dar, S., Ikonomovic, M.D., DeKosky, S.T., and Mufson, E.J. (2007). Cholinergic Forebrain Degeneration in the APPswe/$PS1{\Delta}E9$ Transgenic Mouse. Neurobiol. Dis. 28, 3-15. https://doi.org/10.1016/j.nbd.2007.06.015
  38. Pyo, M.K., Choi, S.-H., Hwang, S.H., Shin, T.J., Lee, B.H., Lee, S.M., Lim, Y.H., Kim, D.H., and Nah, S.Y. (2011). Novel Glycolipoproteins from Ginseng. J. Ginseng Res. 35, 92-103. https://doi.org/10.5142/jgr.2011.35.1.092
  39. Shin, T.J., Kim, H.J., Kwon, B.J., Choi, S.H., Kim, H.B., Hwang, S.H., Lee, B.H., Lee, S.M., Zukin, R.S., Park, J.H., et al. (2012). Gintonin, a ginseng-derived novel ingredient, evokes long-term potentiation through N-methyl-D-aspartic acid receptor activation: involvement of LPA receptors. Mol. Cells 34, 563-572. https://doi.org/10.1007/s10059-012-0254-4
  40. Shiono, S., Kawamoto, K., Yoshida, N., Kondo, T., and Inagami, T. (1993). Neurotransmitter release from lysophosphatidic acid stimulated PC12 cells: involvement of lysophosphatidic acid receptors. Biochem. Biophys. Res. Commun. 193, 667-673. https://doi.org/10.1006/bbrc.1993.1676
  41. Su, C.F., Cheng, J.T., and Liu, I.M. (2007). Increase of acetylcholine release by Panax ginseng root enhances insulin secretion in Wistar rats. Neurosci. Lett. 412, 101-104. https://doi.org/10.1016/j.neulet.2006.10.044
  42. Sun, Y., Nam, J.S., Han, D.H., Kim, N.H., Choi, H.K., Lee, J.K., Rhee, H.J., and Huh, S.O. (2010). Lysophosphatidic acid induces upregulation of Mcl-1 and protects apoptosis in a PTXdependent manner in H19-7 cells. Cell. Signal. 22, 484-494. https://doi.org/10.1016/j.cellsig.2009.11.002
  43. Tabuchi, S., Kume, K., Aihara, M., and Shimizu, T. (2000). Expression of lysophosphatidic acid receptor in rat astrocytes: mitogenic effect and expression of neurotrophic genes. Neurochem Res. 25, 573-582. https://doi.org/10.1023/A:1007542532395
  44. Trimbuch, T., Beed, P., Vogt, J., Schuchmann, S., Maier, N., Kintscher, M., Breustedt, J., Schuelke, M., Streu, N., Kieselmann, O., et al. (2009). Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 138, 1222-1235. https://doi.org/10.1016/j.cell.2009.06.050
  45. Vassar, R., Bennett, B.D., Babu-Khan, S., Kahn, S., Mendiaz, E.A., Denis, P., Teplow, D.B., Ross, S., Amarante, P., Loeloff, R., et al. (1999). Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741. https://doi.org/10.1126/science.286.5440.735
  46. Wang, Q., Shin, E.J., Nguyen, X.K., Li, Q., Bach, J.H., Bing, G., Kim, W.K., and Kim, H.C., Hong, J.S. (2012). Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice. J. Neuroinflammation. 9, 124. https://doi.org/10.1186/1742-2094-9-124
  47. Wong, T.P., Debeir, T., Duff, K., and Cuello, A.C. (1999). Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J. Neurosci. 19, 2706-2716.
  48. Yankner, B.A. (1996). Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16, 921-932. https://doi.org/10.1016/S0896-6273(00)80115-4

Cited by

  1. Plant Lysophosphatidic Acids: A Rich Source for Bioactive Lysophosphatidic Acids and Their Pharmacological Applications vol.39, pp.2, 2016, https://doi.org/10.1248/bpb.b15-00575
  2. Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease vol.101, 2016, https://doi.org/10.1016/j.neuint.2016.10.006
  3. Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene 2017, https://doi.org/10.1007/s12035-017-0638-8
  4. DL0410 Ameliorates Memory and Cognitive Impairments Induced by Scopolamine via Increasing Cholinergic Neurotransmission in Mice vol.22, pp.3, 2017, https://doi.org/10.3390/molecules22030410
  5. Ginseng pharmacology: a new paradigm based on gintonin-lysophosphatidic acid receptor interactions vol.6, 2015, https://doi.org/10.3389/fphar.2015.00245
  6. Gintonin absorption in intestinal model systems 2016, https://doi.org/10.1016/j.jgr.2016.12.007
  7. Nitrosylation of Vesicular Transporters in Brain of Amyloid Precursor Protein/Presenilin 1 Double Transgenic Mice vol.55, pp.4, 2016, https://doi.org/10.3233/JAD-160700
  8. Gintonin Administration is Safe and Potentially Beneficial in Cognitively Impaired Elderly vol.32, pp.1, 2018, https://doi.org/10.1097/WAD.0000000000000213
  9. Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of α-Synuclein via the Nrf2/HO-1 Pathway pp.1559-1182, 2018, https://doi.org/10.1007/s12035-018-1020-1