Journal of Ginseng Research

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

DOI QR Code

Ginseng gintonin alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis through lysophosphatidic acid 1 receptor

  • Nam, Sung Min (Department of Anatomy, College of Veterinary Medicine, Konkuk University) ;
  • Choi, Jong Hee (Department of Science in Korean Medicine, Brain Korea 21 Plus Program, Department of Conversions Medical Science, Graduate School, Kyung Hee University) ;
  • Choi, Sun-Hye (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Cho, Hee-Jung (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Cho, Yeon-Jin (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Rhim, Hyewhon (Center for Neuroscience, Korea Institute of Science and Technology) ;
  • Kim, Hyoung-Chun (Neuropsychopharmacology and Toxicology program, College of Pharmacy, Kangwon National University) ;
  • Cho, Ik-Hyun (Department of Science in Korean Medicine, Brain Korea 21 Plus Program, Department of Conversions Medical Science, Graduate School, Kyung Hee University) ;
  • Kim, Do-Geun (Neurovascular Biology Laboratory, Department of Structure and Function of Neural Network, Korea Brain Research Institute) ;
  • Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
  • Received : 2020.01.03
  • Accepted : 2020.04.24
  • Published : 2021.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS. Methods: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests. Results: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100β-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits. Conclusion: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms.

Keywords

Acknowledgement

This work was supported by the Konkuk Univeristy in 2020.

References

  1. Bucchia M, Ramirez A, Parente V, Simone C, Nizzardo M, Magri F, Dametti S, Corti S. Therapeutic development in amyotrophic lateral sclerosis. Clin Ther 2015;37:668-80. https://doi.org/10.1016/j.clinthera.2014.12.020
  2. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 2006;7:710-23. https://doi.org/10.1038/nrn1971
  3. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62. https://doi.org/10.1038/362059a0
  4. Boillee S, Cleveland DW. Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1. J Clin Invest 2008;118:474-8. https://doi.org/10.1172/JCI34613
  5. Bordt EA, Polster BM. NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair? Free Radic Biol Med 2014;76:34-46. https://doi.org/10.1016/j.freeradbiomed.2014.07.033
  6. McGeer EG, McGeer PL. Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis. BioDrugs 2005;19:31-7. https://doi.org/10.2165/00063030-200519010-00004
  7. Lacomblez L, Bensimon G, Leigh PN, Debove C, Bejuit R, Truffinet P, Meininger V. ALS Study Groups I and II. Long-term safety of riluzole in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2002;3:23-9. https://doi.org/10.1080/146608202317576507
  8. Nah SY. Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors. Front Physiol 2014;5:98. https://doi.org/10.3389/fphys.2014.00098
  9. Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol 1969;9:419-30. https://doi.org/10.1146/annurev.pa.09.040169.002223
  10. Hwang SH, Shin TJ, Choi SH, Cho HJ, Lee BH, Pyo MK, Lee JH, Kang J, Kim HJ, Park CW, et al. 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 2012;33:151-62. https://doi.org/10.1007/s10059-012-2216-z
  11. Choi SH, Jung SW, Lee BH, Kim HJ, Hwang SH, Kim HK, Nah SY. Ginseng pharmacology: a new paradigm based on gintonin-lysophosphatidic acid receptor interactions. Front Pharmacol 2015;6:245. https://doi.org/10.3389/fphar.2015.00245
  12. Hwang SH, Shin EJ, Shin TJ, Lee BH, Choi SH, Kang J, Kim HJ, Kwon SH, Jang CG, Lee JH, et al. Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing. J Alzheimer's Dis 2012;31:207-23. https://doi.org/10.3233/JAD-2012-120439
  13. Moon J, Choi SH, Shim JY, Park HJ, Oh MJ, Kim M, Nah SY. Gintonin administration is safe and potentially beneficial in cognitively impaired elderly. Alzheimer Dis Assoc Disord 2018;32:85-7. https://doi.org/10.1097/WAD.0000000000000213
  14. Choi JH, Jang M, Oh S, Nah SY, Cho IH. Multi-target protective effects of gintonin in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-mediated model of Parkinson's disease via lysophosphatidic acid receptors. Front Pharmacol 2018;9:515. https://doi.org/10.3389/fphar.2018.00515
  15. Jo MG, Ikram M, Jo MH, Yoo L, Chung KC, Nah SY, Hwang H, Rhim H, Kim MO. Gintonin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of a-synuclein via the Nrf2/HO-1 pathway. Mol Neurobiol 2019;56:39-55. https://doi.org/10.1007/s12035-018-1020-1
  16. Jang M, Choi JH, Chang Y, Lee SJ, Nah SY, Cho IH. Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain Behav Immun 2019;80:146-62. https://doi.org/10.1016/j.bbi.2019.03.001
  17. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994;264:1772-5. https://doi.org/10.1126/science.8209258
  18. Choi SH, Jung SW, Kim HS, Kim HJ, Lee BH, Kim JY, Kim JH, Hwang SH, Rhim H, Kim HC, et al. A brief method for preparation of gintonin-enriched fraction from ginseng. J Ginseng Res 2015;39:398-405. https://doi.org/10.1016/j.jgr.2015.05.002
  19. Nam SM, Hwang H, Seo M, Chang BJ, Kim HJ, Choi SH, Rhim H, Kim HC, Cho IH, Nah SY. Gintonin attenuates D-galactose-induced hippocampal senescence by improving long-term hippocampal potentiation, neurogenesis, and cognitive functions. Gerontology 2018;64:562-75. https://doi.org/10.1159/000491113
  20. Hatzipetros T, Kidd JD, Moreno AJ, Thompson K, Gill A, Vieira FG. A quick phenotypic neurological scoring system for evaluating disease progression in the SOD1-G93A mouse model of ALS. J Vis Exp 2015;104:e53257.
  21. Seo JS, Choi J, Leem YH, Han PL. Rosmarinic acid alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurobiol 2015;24:341-50. https://doi.org/10.5607/en.2015.24.4.341
  22. Cai M, Choi SM, Song BK, Son I, Kim S, Yang EJ. Scolopendra subspinipes mutilans attenuates neuroinflammation in symptomatic hSOD1(G93A) mice. J Neuroinflammation 2013;10:131. https://doi.org/10.1186/1742-2094-10-131
  23. Nam SM, Seo M, Seo JS, Rhim H, Nahm SS, Cho IH, Chang BJ, Kim HJ, Choi SH, Nah SY. Ascorbic acid mitigates D-galactose-induced brain aging by increasing hippocampal neurogenesis and improving memory function. Nutrients 2019;11:176. https://doi.org/10.3390/nu11010176
  24. Nam SM, Chang BJ, Kim JH, Nahm SS, Lee JH. Ascorbic acid ameliorates lead-induced apoptosis in the cerebellar cortex of developing rats. Brain Res 2018;1686:10-8. https://doi.org/10.1016/j.brainres.2018.02.014
  25. Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 2013;16:571-9. https://doi.org/10.1038/nn.3357
  26. Philips T, Bento-Abreu A, Nonneman A, Haeck W, Staats K, Geelen V, Hersmus N, Kusters B, Van Den Bosch L, Van Damme P, et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 2013;136:471-82. https://doi.org/10.1093/brain/aws339
  27. Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, David S. Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci 2009;29:610-9. https://doi.org/10.1523/JNEUROSCI.5443-08.2009
  28. Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JH, et al. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 2014;111:1035-42.
  29. 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;138:1222-35. https://doi.org/10.1016/j.cell.2009.06.050
  30. 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;113:1493-500. https://doi.org/10.1152/jn.00667.2014
  31. Matas-Rico E, Garcia-Diaz B, Llebrez-Zayas P, Lopez-Barroso D, Santin L, Pedraza C, Smith-Fernandez A, Fernandez-Llebrez P, Tellez T, Redondo M, et al. Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus. Mol Cell Neurosci 2008;39:342-55. https://doi.org/10.1016/j.mcn.2008.07.014
  32. Castilla-Ortega E, Pedraza C, Chun J, de Fonseca FR, Estivill-Torrus G, Santin LJ. Hippocampal c-Fos activation in normal and LPA1-null mice after two object recognition tasks with different memory demands. Behav Brain Res 2012;232:400-5. https://doi.org/10.1016/j.bbr.2012.04.018
  33. Goldshmit Y, Munro K, Leong SY, Pebay A, Turnley AM. LPA receptor expression in the central nervous system in health and following injury. Cell Tissue Res 2010;341:23-32. https://doi.org/10.1007/s00441-010-0977-5
  34. Kim HJ, Kim DJ, Shin EJ, Lee BH, Choi SH, Hwang SH, Rhim H, Cho IH, Kim HC, Nah SY. 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;1:56-65.
  35. Kim S, Kim MS, Park K, Kim HJ, Jung SW, Nah SY, Han JS, Chung C. Hippocampus-dependent cognitive enhancement induced by systemic gintonin administration. J Ginseng Res 2016;40:55-61. https://doi.org/10.1016/j.jgr.2015.05.001
  36. Garcia-Fernandez M, Castilla-Ortega E, Pedraza C, Blanco E, Hurtado-Guerrero I, Barbancho MA, Chun J, Rodriguez-de-Fonseca F, Estivill-Torrus G, Santin Nunez LJ. Chronic immobilization in the malpar1 knockout mice increases oxidative stress in the hippocampus. Int J Neurosci 2012;122:583-9. https://doi.org/10.3109/00207454.2012.693998
  37. Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schoneich C, et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 2008;118:659-70. https://doi.org/10.1172/JCI34060
  38. Ascherio A, Weisskopf MG, O'reilly EJ, Jacobs EJ, McCullough ML, Calle EE, Cudkowicz M, Thun MJ. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann Neurol 2005;57:104-10. https://doi.org/10.1002/ana.20316
  39. Molina JA, de Bustos F, Jimenez-Jimenez FJ, Gomez-Escalonilla C, Garcia-Redondo A, Esteban J, Guerrero-Sola A, del Hoyo P, Martinez-Salio A, Ramirez-Ramos C, et al. Serum levels of coenzyme Q10 in patients with amyotrophic lateral sclerosis. J Neural Transm 2000;107:1021-6. https://doi.org/10.1007/s007020070050
  40. Lee J, Hyeon SJ, Im H, Ryu H, Kim Y, Ryu H. Astrocytes and microglia as noncell autonomous players in the pathogenesis of ALS. Exp Neurobiol 2016;25:233-40. https://doi.org/10.5607/en.2016.25.5.233
  41. Cai M, Lee SH, Yang EJ. Bojungikgi-tang improves muscle and spinal cord function in an amyotrophic lateral sclerosis model. Mol Neurobiol 2019;56:2394-407. https://doi.org/10.1007/s12035-018-1236-0
  42. Dwyer BE, Lu SY, Nishimura RN. Heme oxygenase in the experimental ALS mouse. Exp Neurol 1998;150:206-12. https://doi.org/10.1006/exnr.1997.6763
  43. Nam SM, Choi SH, Cho HJ, Seo JS, Choi M, Nahm SS, Chang BJ, Nah SY. Ginseng gintonin attenuates lead-induced rat cerebellar impairments during gestation and lactation. Biomolecules 2020;10:E385.