Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Gintonin influences the morphology and motility of adult brain neurons via LPA receptors

  • Kim, Do-Geun (Dementia Research Group, Korea Brain Research Institute) ;
  • Kim, Hyeon-Joong (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) ;
  • Nam, Sung Min (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Kim, Hyoung-Chun (Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University) ;
  • Rhim, Hyewhon (Center for Neuroscience, Korea Institute of Science and Technology) ;
  • Cho, Ik-Hyun (Department of Convergence Medical Science, Brain Korea 21 Plus Program, and Institute of Korean Medicine, College of Korean Medicine, Kyung Hee University) ;
  • Rhee, Man Hee (Laboratory of Veterinary Physiology & Cell Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
  • Received : 2020.04.23
  • Accepted : 2020.06.30
  • Published : 2021.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Gintonin is an exogenous ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. LPA induces in vitro morphological changes and migration through neuronal LPA1 receptor. Recently, we reported that systemic administration of gintonin increases blood-brain barrier (BBB) permeability via the paracellular pathway and its binding to brain neurons. However, little is known about the influences of gintonin on in vivo neuron morphology and migration in the brain. Materials and methods: We examined the effects of gintonin on in vitro migration and morphology using primary hippocampal neural precursor cells (hNPC) and in vivo effects of gintonin on adult brain neurons using real time microscopic analysis and immunohistochemical analysis to observe the morphological and locational changes induced by gintonin treatment. Results: We found that treating hNPCs with gintonin induced morphological changes with a cell rounding following cell aggregation and return to individual neurons with time relapses. However, the in vitro effects of gintonin on hNPCs were blocked by the LPA1/3 receptor antagonist, Ki16425, and Rho kinase inhibitor, Y27632. We also examined the in vivo effects of gintonin on the morphological changes and migration of neurons in adult mouse brains using anti-NeuN and -neurofilament H antibodies. We found that acute intravenous administration of gintonin induced morphological and migrational changes in brain neurons. Gintonin induced some migrations of neurons with shortened neurofilament H in the cortex. The in vivo effects of gintonin were also blocked by Ki16425. Conclusion: The present report raises the possibility that gintonin could enter the brain and exert its influences on the migration and morphology of adult mouse brain neurons and possibly explains the therapeutic effects of neurological diseases behind the gintonin administration.

Keywords

Acknowledgement

This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, and ICT (NRF-2016M3C7A1913894 to S.Y. Nah and NRF-2018R1C1B6001055 to D.G. Kim) and KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (20-BR-02-11 to D.G. Kim).

References

  1. Choi JW, Chun J. Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta 2013;1831(1):20-32. https://doi.org/10.1016/j.bbalip.2012.07.015
  2. Choi JW, Herr DR, Noguchi K, Yung YC, Lee C-W, Mutoh T, Lin M-E, Teo ST, Park KE, Mosley AN, et al. LPA receptors: subtypes and biological actions. Ann Rev Pharmacol Toxicol 2010;50(1):157-86. https://doi.org/10.1146/annurev.pharmtox.010909.105753
  3. Chun J. Lysophospholipids in the nervous system. Prostaglandins Other Lipid Mediat 2005;77(1-4):46-51. https://doi.org/10.1016/j.prostaglandins.2004.09.009
  4. Pilpel Y, Segal M. The role of LPA1 in formation of synapses among cultured hippocampal neurons. J Neurochem 2006;97(5):1379-92. https://doi.org/10.1111/j.1471-4159.2006.03825.x
  5. Im D-S, Nah S-Y. Yin and Yang of ginseng pharmacology: ginsenosides vs gintonin. Acta Pharmacol Sin 2013;34(11):1367-73. https://doi.org/10.1038/aps.2013.100
  6. Choi S-H, Lee B-H, Kim H-J, Jung S-W, Kim H-S, Shin H-C, Lee J-H, Kim H-C, Rhim H, Hwang S-H, et al. Ginseng gintonin activates the human cardiac delayed rectifier K(+) channel: involvement of Ca(2+)/calmodulin binding sites. Mol Cells 2014;37(9):656-63. https://doi.org/10.14348/MOLCELLS.2014.0087
  7. Hwang SH, Lee BH, Choi SH, Kim HJ, Jung SW, Kim HS, Shin HC, Park HJ, Park KH, Lee MK, et al. Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, stimulates neurotransmitter release. Neurosci Lett 2015;584:356-61. https://doi.org/10.1016/j.neulet.2014.11.007
  8. Kim D-G, Jang M, Choi S-H, Kim H-J, Jhun H, Kim H-C, Rhim H, Cho I-H, Nah SY. Gintonin, a ginseng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery. Int J Biol Macromol 2018;114:1325-37. https://doi.org/10.1016/j.ijbiomac.2018.03.158
  9. Park H, Kim S, Rhee J, Kim HJ, Han JS, Nah SY, Chung C. Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. J Neurophysiol 2015;113(5):1493-500. https://doi.org/10.1152/jn.00667.2014
  10. Pyo MK, Choi SH, Shin TJ, Hwang SH, Lee BH, Kang J, Kim HJ, Lee SH, Nah SY. A simple method for the preparation of crude gintonin from ginseng root, stem, and leaf. J Ginseng Res 2011;35(2):209-18. https://doi.org/10.5142/jgr.2011.35.2.209
  11. Choi SH, Hong MK, Kim HJ, Ryoo N, Rhim H, Nah SY, Kang LW. Structure of ginseng major latex-like protein 151 and its proposed lysophosphatidic acid-binding mechanism. Acta Crystallogr D Biol Crystallogr 2015;71(Pt 5):1039-50. https://doi.org/10.1107/S139900471500259X
  12. Kim H-J, Kim D-J, Shin E-J, Lee B-H, Choi S-H, Hwang S-H, Rhim H, Cho I-H, Kim H-C, Nah S-Y, et al. 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. Neurochem Int 2016;101:56-65. https://doi.org/10.1016/j.neuint.2016.10.006
  13. Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci 2003;6(12):1292-9. https://doi.org/10.1038/nn1157
  14. Contos JJ, Ishii I, Fukushima N, Kingsbury MA, Ye X, Kawamura S, Brown JH, Chun J. Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). Mol Cell Biol 2002;22(19):6921-9. https://doi.org/10.1128/MCB.22.19.6921-6929.2002
  15. Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, Hemmati P, et al. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci 2003;24(4):1170-9. https://doi.org/10.1016/j.mcn.2003.09.001
  16. Dubin AE, Herr DR, Chun J. Diversity of lysophosphatidic acid receptor-mediated intracellular calcium signaling in early cortical neurogenesis. J Neurosci 2010;30(21):7300-9. https://doi.org/10.1523/JNEUROSCI.6151-09.2010
  17. Yamane M, Furuta D, Fukushima N. Lysophosphatidic acid influences initial neuronal polarity establishment. Neurosci Lett 2010;480(2):154-7. https://doi.org/10.1016/j.neulet.2010.06.031
  18. Sigal YJ, McDermott MI, Morris AJ. Integral membrane lipid phosphatases/phosphotransferases: common structure and diverse functions. Biochem J 2005;387(Pt 2):281-93. https://doi.org/10.1042/BJ20041771
  19. Fukushima N, Ishii I, Habara Y, Allen CB, Chun J. Dual regulation of actin rearrangement through lysophosphatidic acid receptor in neuroblast cell lines: actin depolymerization by Ca(2+)-alpha-actinin and polymerization by rho. Mol Biol Cell 2002;13(8):2692-705. https://doi.org/10.1091/mbc.01-09-0465
  20. Nogaroli L, Yuelling LM, Dennis J, Gorse K, Payne SG, Fuss B. Lysophosphatidic acid can support the formation of membranous structures and an increase in MBP mRNA levels in differentiating oligodendrocytes. Neurochem Res 2009;34(1):182-93. https://doi.org/10.1007/s11064-008-9772-z
  21. Trimbuch T, Beed P, Vogt J, Schuchmann S, Maier N, Kintscher M, Breustedt J, Schuelke M, Streu N, Kieselmann O, et al. Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 2009;138(6):1222-35. https://doi.org/10.1016/j.cell.2009.06.050
  22. Ladron de Guevara-Miranda D, Moreno-Fernandez RD, Gil-Rodriguez S, Rosell-Valle C, Estivill-Torrus G, Serrano A, Pavon FJ, Rodriguez de Fonseca F, Santin LJ, Castilla-Ortega E. Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory. Addict Biol 2019;24(3):458-70. https://doi.org/10.1111/adb.12612
  23. Kim S, Kim M-S, Park K, Kim H-J, Jung S-W, Nah S-Y, Han J-S, Chung C. Hippocampus-dependent cognitive enhancement induced by systemic gintonin administration. J Ginseng Res 2016;40(1):55-61. https://doi.org/10.1016/j.jgr.2015.05.001
  24. Gotoh L, Yamada M, Hattori K, Sasayama D, Noda T, Yoshida S, Kunugi H, Yamada M. Lysophosphatidic acid levels in cerebrospinal fluid and plasma samples in patients with major depressive disorder. Heliyon 2019;5(5):e01699. https://doi.org/10.1016/j.heliyon.2019.e01699