Journal of Ginseng Research

  • 제48권1호
  • /
  • Pages.59-67
  • /
  • 2024
  • /
  • 1226-8453(pISSN)
  • /
  • 2093-4947(eISSN)
고려인삼학회 (The Korean Society of Ginseng)
권호 표지
DOI QR코드

DOI QR Code

Panaxcerol D from Panax ginseng ameliorates the memory impairment induced by cholinergic blockade or Aβ25-35 peptide in mice

  • Keontae Park (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Ranhee Kim (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Kyungnam Cho (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Chang Hyeon Kong (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Mijin Jeon (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Woo Chang Kang (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Seo Yun Jung (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Dae Sik Jang (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University) ;
  • Jong Hoon Ryu (Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University)
  • 투고 : 2023.01.25
  • 심사 : 2023.08.11
  • 발행 : 2024.01.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: Alzheimer's disease (AD) has memory impairment associated with aggregation of amyloid plaques and neurofibrillary tangles in the brain. Although anti-amyloid β (Aβ) protein antibody and chemical drugs can be prescribed in the clinic, they show adverse effects or low effectiveness. Therefore, the development of a new drug is necessarily needed. We focused on the cognitive function of Panax ginseng and tried to find active ingredient(s). We isolated panaxcerol D, a kind of glycosyl glyceride, from the non-saponin fraction of P. ginseng extract. Methods: We explored effects of acute or sub-chronic administration of panaxcerol D on cognitive function in scopolamine- or Aβ25-35 peptide-treated mice measured by several behavioral tests. After behavioral tests, we tried to unveil the underlying mechanism of panaxcerol D on its cognitive function by Western blotting. Results: We found that pananxcerol D reversed short-term, long-term and object recognition memory impairments. The decreased extracellular signal-regulated kinases (ERK) or Ca2+/calmodulin-dependent protein kinase II (CaMKII) in scopolamine-treated mice was normalized by acute administration of panaxcerol D. Glial fibrillary acidic protein (GFAP), caspase 3, NF-kB p65, synaptophysin and brainderived neurotrophic factor (BDNF) expression levels in Aβ25-35 peptide-treated mice were modulated by sub-chronic administration of panaxcerol D. Conclusion: Pananxcerol D could improve memory impairments caused by cholinergic blockade or Aβ accumulation through increased phosphorylation level of ERK or its anti-inflammatory effect. Thus, panaxcerol D as one of non-saponin compounds could be used as an active ingredient of P. ginseng for improving cognitive function.

키워드

과제정보

This research was supported by the 2021 from the Korean Society of Ginseng.

참고문헌

  1. Gale SA, Acar D, Daffner KR. Dementia. Epub 2018/02/10 Am J Med 2018;131(10):1161-9. https://doi.org/10.1016/j.amjmed.2018.01.022.PubMed PMID: 29425707.
  2. Ljubenkov PA, Geschwind MD. Dementia. Epub 2016/09/20 Semin Neurol 2016;36(4):397-404. https://doi.org/10.1055/s-0036-1585096. PubMedPMID: 27643909.
  3. Gallardo G, Holtzman DM. Amyloid-b and tau at the crossroads of alzheimer's disease. Epub 2020/02/26 Adv Exp Med Biol 2019;1184:187-203. https://doi.org/10.1007/978-981-32-9358-8_16. PubMed PMID: 32096039.
  4. Sharma K. Cholinesterase inhibitors as Alzheimer's therapeutics (Review). Epub 2019/07/02 Mol Med Rep 2019;20(2):1479-87. https://doi.org/10.3892/mmr.2019.10374. PubMed PMID: 31257471; PubMed Central PMCID:PMCPMC6625431.
  5. Tayeb HO, Yang HD, Price BH, Tarazi FI. Pharmacotherapies for Alzheimer's disease: beyond cholinesterase inhibitors. Epub 2011/12/27 Pharmacol Ther 2012;134(1):8-25. https://doi.org/10.1016/j.pharmthera.2011.12.002.PubMed PMID: 22198801.
  6. Park HJ, Kim DH, Park SJ, Kim JM, Ryu JH. Ginseng in traditional herbal prescriptions. Epub 2013/05/30 J Ginseng Res 2012;36(3):225-41. https:// doi.org/10.5142/jgr.2012.36.3.225. PubMed PMID: 23717123; PubMed Central PMCID: PMCPMC3659587.
  7. Kang S, Min H. Ginseng, the 'immunity boost': the effects of panax ginseng on immune system. Epub 2013/05/30 J Ginseng Res 2012;36(4):354-68. https://doi.org/10.5142/jgr.2012.36.4.354. PubMed PMID: 23717137; PubMed Central PMCID: PMCPMC3659612.
  8. Kiefer D, Pantuso T. Panax ginseng. Am Fam Physician 2003;68(8):1539-42. Epub 2003/11/05. PubMed PMID: 14596440.
  9. Razgonova MP, Veselov VV, Zakharenko AM, Golokhvast KS, Nosyrev AE, Cravotto G, Tsatsakis A, Spandidos DA. Panax ginseng components and the pathogenesis of Alzheimer's disease (Review). Epub 2019/03/01 Mol Med Rep 2019;19(4):2975-98. https://doi.org/10.3892/mmr.2019.9972. PubMed PMID: 30816465; PubMed Central PMCID: PMCPMC6423617.
  10. Wang H, Lv J, Jiang N, Huang H, Wang Q, Liu X. Ginsenoside Re protects against chronic restraint stress-induced cognitive deficits through regulation of NLRP3 and Nrf2 pathways in mice. Epub 2021/03/31 Phytother Res: PTR 2021. https://doi.org/10.1002/ptr.6947. PubMed PMID: 33783035.
  11. Kim J, Shim J, Lee S, Cho WH, Hong E, Lee JH, Han JS, Lee HJ, Lee KW. Rg3-enriched ginseng extract ameliorates scopolamine-induced learning deficits in mice. Epub 2016/02/19 BMC Compl Alternative Med 2016;16:66. https://doi.org/10.1186/s12906-016-1050-z. PubMed PMID: 26887326; PubMed Central PMCID: PMCPMC4758096.
  12. Changhong K, Peng Y, Yuan Z, Cai J. Ginsenoside Rb1 protected PC12 cells from Ab(25-35)-induced cytotoxicity via PPARg activation and cholesterol reduction. Epub 2020/12/29 Eur J Pharmacol 2021;893:173835. https://doi.org/10.1016/j.ejphar.2020.173835. PubMed PMID: 33359145.
  13. Lee B, Sur B, Park J, Kim SH, Kwon S, Yeom M, Shim I, Lee H, Hahm DH. Ginsenoside rg3 alleviates lipopolysaccharide-induced learning and memory impairments by anti-inflammatory activity in rats. Epub 2013/11/19 Biomol Therapeut 2013;21(5):381-90. https://doi.org/10.4062/biomolther.2013.053. PubMed PMID: 24244826; PubMed Central PMCID: PMCPMC3825202.
  14. Fang F, Chen X, Huang T, Lue L-F, Luddy JS, Yan SS. Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta (BBA) - Mol Basis Dis 2012;1822(2):286-92. https://doi.org/10.1016/j.bbadis.2011.10.004.
  15. 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. Epub 2012/05/01 J Alzheim Dis: JAD 2012;31(1):207-23. https://doi.org/10.3233/jad-2012-120439. PubMed PMID: 22543851.
  16. Cha BJ, Park JH, Shrestha S, Baek NI, Lee SM, Lee TH, Kim J, Kim GS, Kim SY, Lee DY. Glycosyl glycerides from hydroponic Panax ginseng inhibited NO production in lipopolysaccharide-stimulated RAW264.7 cells. Epub 2015/06/ 06 J Ginseng Res 2015;39(2):162-8. https://doi.org/10.1016/j.jgr.2014.10.005. PubMed PMID: 26045690; PubMed Central PMCID: PMCPMC4452534.
  17. Kim G-s. Development of functional foods and beauty cosmetic materials using ginseng and medicinal plants. In: 한국약용작물학회 학술대회논문집 2018; 2018. p. 1-16. 2.
  18. Kaminsky YG, Marlatt MW, Smith MA, Kosenko EA. Subcellular and metabolic examination of amyloid-beta peptides in Alzheimer disease pathogenesis: evidence for Abeta(25-35). Epub 2009/09/16 Exp Neurol 2010;221(1):26-37. https://doi.org/10.1016/j.expneurol.2009.09.005. PubMed PMID: 19751725.
  19. Kim MJ, Jung JE, Lee S, Cho EJ, Kim HY. Effects of the fermented Zizyphus jujuba in the amyloid b(25-35)-induced Alzheimer's disease mouse model. Epub 2021/04/13 Nutr Res Pract 2021;15(2):173-86. https://doi.org/10.4162/ nrp.2021.15.2.173. PubMed PMID: 33841722; PubMed Central PMCID: PMCPMC8007403.
  20. Paxinos G, Franklin KB. The mouse brain in stereotaxic coordinates. Third. Academic Press; 2008.
  21. Kraeuter AK, Guest PC, Sarnyai Z. The Y-maze for assessment of spatial working and reference memory in mice. Epub 2018/12/12 Methods Mol Biol 2019;1916:105-11. https://doi.org/10.1007/978-1-4939-8994-2_10. PubMed PMID: 30535688.
  22. Bae HJ, Kim J, Jeon SJ, Kim J, Goo N, Jeong Y, Cho K, Cai M, Jung SY, Kwon KJ, et al. Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice. Epub 2020/05/04 J Ethnopharmacol 2020;258:112923. https://doi.org/10.1016/j.jep.2020.112923. PubMed PMID: 32360798.
  23. Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. Epub 2017/09/12 J Vis Exp 2017;126. https://doi.org/10.3791/55718. PubMed PMID: 28892027; PubMed Central PMCID: PMCPMC5614391.
  24. Koo B, Bae HJ, Goo N, Kim J, Kim J, Cai M, Jung IH, Cho K, Jung SY, Chang SW, et al. A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice. Epub 2019/11/13 J Pharm Pharmacol 2020;72(1):149-60. https://doi.org/10.1111/jphp.13199. PubMed PMID: 31713882.
  25. Kim JY, Lee HK, Jang JY, Yoo JK, Seong YH. Ilex latifolia prevents amyloid b protein (25-35)-induced memory impairment by inhibiting apoptosis and tau phosphorylation in mice. Epub 2015/08/21 J Med Food 2015;18(12):1317-26. https://doi.org/10.1089/jmf.2015.3443. PubMed PMID: 26291170; PubMed Central PMCID: PMCPMC4685495.
  26. Kim J, Seo YH, Kim J, Goo N, Jeong Y, Bae HJ, Jung SY, Lee J, Ryu JH. Casticin ameliorates scopolamine-induced cognitive dysfunction in mice. Epub 2020/ 05/08 J Ethnopharmacol 2020;259:112843. https://doi.org/10.1016/j.jep.2020.112843. PubMed PMID: 32380246.
  27. Sarter M, Bodewitz G, Stephens DN. Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines. Epub 1988/01/01 Psychopharmacology 1988;94(4):491-5. https://doi.org/10.1007/bf00212843. PubMed PMID: 2836875.
  28. Kim J, Kim SH, Lee DS, Lee DJ, Kim SH, Chung S, Yang HO. Effects of fermented ginseng on memory impairment and b-amyloid reduction in Alzheimer's disease experimental models. Epub 2013/05/30 J Ginseng Res 2013;37(1): 100-7. https://doi.org/10.5142/jgr.2013.37.100. PubMed PMID: 23717163; PubMed Central PMCID: PMCPMC3659620.
  29. Choi JG, Kim N, Huh E, Lee H, Oh MH, Park JD, Pyo MK, Oh MS. White ginseng protects mouse hippocampal cells against amyloid-beta oligomer toxicity. Epub 2017/01/24 Phytother Res 2017;31(3):497-506. https://doi.org/ 10.1002/ptr.5776. PubMed PMID: 28112442.
  30. Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in Alzheimer disease. Epub 2008/06/27 Alzheimer Dis Assoc Disord 2008;22(3):222-6. https://doi.org/10.1097/WAD.0b013-31816c92-6. PubMed PMID: 18580589.
  31. Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M. Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with Korean red ginseng. Epub 2011/11/01 J Ginseng Res 2011;35(4):457-61. https://doi.org/10.5142/jgr.2011.35.4.457. PubMed PMID: 23717092; PubMed Central PMCID: PMCPMC3659550.
  32. Heo JH, Park MH, Lee JH. Effect of Korean red ginseng on cognitive function and quantitative EEG in patients with alzheimer's disease: a preliminary study. Epub 2016/03/15 J Altern Complement Med 2016;22(4):280-5. https://doi.org/10.1089/acm.2015.0265. PubMed PMID: 26974484.
  33. Lu J, Wang X, Wu A, Cao Y, Dai X, Liang Y, Li X. Ginsenosides in central nervous system diseases: pharmacological actions, mechanisms, and therapeutics. Epub 2022/01/28 Phytother Res 2022;36(4):1523-44. https://doi.org/ 10.1002/ptr.7395. PubMed PMID: 35084783.
  34. Dhamodharan J, Sekhar G, Muthuraman A. Epidermal growth factor receptor kinase inhibitor ameliorates b-amyloid oligomer-induced alzheimer disease in Swiss albino mice. Epub 2022/08/27 Molecules 2022;27(16). https://doi.org/10.3390/molecules27165182. PubMed PMID: 36014421; PubMed Central PMCID: PMCPMC9412386.
  35. Liu M, Zeng M, Wang S, Cao B, Guo P, Zhang Y, Jia J, Zhang Q, Zhang B, Wang R, et al. Thymidine and 2'-deoxyuridine reduce microglial activation and improve oxidative stress damage by modulating glycolytic metabolism on the Ab(25-35)-induced brain injury. Epub 2022/08/24 Arch Biochem Biophys 2022;729:109377. https://doi.org/10.1016/j.abb.2022.109377. PubMed PMID: 35998686.
  36. Khan R, Kulasiri D, Samarasinghe S. A multifarious exploration of synaptic tagging and capture hypothesis in synaptic plasticity: development of an integrated mathematical model and computational experiments. Epub 2022/10/ 25 J Theor Biol 2023;556:111326. https://doi.org/10.1016/j.jtbi.2022.111326. PubMed PMID: 36279957.
  37. Jeon SJ, Kim B, Park HJ, Zhang J, Kwon Y, Kim DH, Ryu JH. The ameliorating effect of 1-palmitoyl-2-linoleoyl-3-acetylglycerol on scopolamine-induced memory impairment via acetylcholinesterase inhibition and LTP activation. Epub 2017/02/01 Behav Brain Res 2017;324:58-65. https://doi.org/10.1016/j.bbr.2017.01.040. PubMed PMID: 28137622.
  38. Kim DH, Kim S, Jeon SJ, Son KH, Lee S, Yoon BH, Cheong JH, Ko KH, Ryu JH. The effects of acute and repeated oroxylin A treatments on Abeta(25-35)-induced memory impairment in mice. Epub 2008/07/16 Neuropharmacology 2008;55(5):639-47. https://doi.org/10.1016/j.neuropharm.2008.05.019. PubMed PMID: 18620712.
  39. Luo SM, Li LY, Guo LZ, Wang L, Wang YF, Chen N, Wang E. Dexmedetomidine exerts an anti-inflammatory effect via a2 adrenoceptors to alleviate cognitive dysfunction in 5xFAD mice. Epub 2022/10/08 Front Aging Neurosci 2022;14: 978768. https://doi.org/10.3389/fnagi.2022.978768. PubMed PMID: 36204551; PubMed Central PMCID: PMCPMC9531904.
  40. Brenner M. Role of GFAP in CNS injuries. Epub 2014/02/11 Neurosci Lett 2014;565:7-13. https://doi.org/10.1016/j.neulet.2014.01.055. PubMed PMID: 24508671; PubMed Central PMCID: PMCPMC4049287.
  41. Xu K, Malouf AT, Messing A, Silver J. Glial fibrillary acidic protein is necessary for mature astrocytes to react to beta-amyloid. Epub 1999/02/24 Glia 1999;25(4):390-403. https://doi.org/10.1002/(sici)1098-1136(19990215)25: 4<390::aid-glia8>3.0.co;2-7. PubMed PMID: 10028921.
  42. Liedtke W, Edelmann W, Chiu FC, Kucherlapati R, Raine CS. Experimental autoimmune encephalomyelitis in mice lacking glial fibrillary acidic protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion. Epub 1998/01/09. PubMed PMID: 9422542; PubMed Central PMCID: PMCPMC1858102 Am J Pathol 1998;152(1):251-9.
  43. Mouser PE, Head E, Ha KH, Rohn TT. Caspase-mediated cleavage of glial fibrillary acidic protein within degenerating astrocytes of the Alzheimer's disease brain. Epub 2006/03/02 Am J Pathol 2006;168(3):936-46. https://doi.org/10.2353/ajpath.2006.050798. PubMed PMID: 16507909; PubMed Central PMCID: PMCPMC1606516.
  44. Snow WM, Albensi BC. Neuronal gene targets of NF-kB and their dysregulation in alzheimer's disease. Epub 2016/11/25 Front Mol Neurosci 2016;9:118. https://doi.org/10.3389/fnmol.2016.00118. PubMed PMID: 27881951; PubMed Central PMCID: PMCPMC5101203.
  45. Janz R, Sudhof TC, Hammer RE, Unni V, Siegelbaum SA, Bolshakov VY. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Epub 1999/12/14 Neuron 1999;24(3):687-700. https://doi.org/10.1016/s0896-6273(00)81122-8. PubMed PMID: 10595519.
  46. Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. Epub 1997/08/01 J Neuropathol Exp Neurol 1997;56(8):933-44. https://doi.org/10.1097/00005072-199708000-00011. PubMed PMID: 9258263.
  47. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Epub 2016/04/02 Science (New York, NY) 2016;352(6286):712-6. https://doi.org/10.1126/science.aad8373. PubMed PMID: 27033548; PubMed Central PMCID: PMCPMC5094372.
  48. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. Epub 2006/10/06 J Neurosci: Off J Soc Neurosci 2006;26(40): 10129-40. https://doi.org/10.1523/jneurosci.1202-06.2006. PubMed PMID: 17021169; PubMed Central PMCID: PMCPMC6674618.
  49. Chang CH, Lin CH, Lane HY. Machine learning and novel biomarkers for the diagnosis of alzheimer's disease. Epub 2021/04/04 Int J Mol Sci 2021;22(5). https://doi.org/10.3390/ijms22052761. PubMed PMID: 33803217; PubMed Central PMCID: PMCPMC7963160.
  50. Park SJ, Lee D, Kim D, Lee M, In G, Han ST, Kim SW, Lee MH, Kim OK, Lee J. The non-saponin fraction of Korean Red Ginseng (KGC05P0) decreases glucose uptake and transport in vitro and modulates glucose production via downregulation of the PI3K/AKT pathway in vivo. Epub 2020/03/10 J Ginseng Res 2020;44(2):362-72. https://doi.org/10.1016/j.jgr.2019.12.004. PubMed PMID: 32148419; PubMed Central PMCID: PMCPMC7031776.
  51. Cho DE, Choi GM, Lee YS, Hong JP, Yeom M, Lee B, Hahm DH. Long-term administration of red ginseng non-saponin fraction rescues the loss of skeletal muscle mass and strength associated with aging in mice. Epub 2022/09/13 J Ginseng Res 2022;46(5):657-65. https://doi.org/10.1016/j.jgr.2021.12.001. PubMed PMID: 36090680; PubMed Central PMCID: PMCPMC9459129.
  52. Yamazaki M, Hirakura K, Miyaichi Y, Imakura K, Kita M, Chiba K, Mohri T. Effect of polyacetylenes on the neurite outgrowth of neuronal culture cells and scopolamine-induced memory impairment in mice. Epub 2002/01/05 Biol Pharm Bull 2001;24(12):1434-6. https://doi.org/10.1248/bpb.24.1434. PubMed PMID: 11767118.
  53. Jakaria M, Azam S, Go EA, Uddin MS, Jo SH, Choi DK. Biological evidence of gintonin efficacy in memory disorders. Epub 2020/10/03 Pharmacol Res 2021;163:105221. https://doi.org/10.1016/j.phrs.2020.105221. PubMed PMID: 33007419.
  54. 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. Epub 2016/02/05 J Ginseng Res 2016;40(1):55-61. https://doi.org/10.1016/j.jgr.2015.05.001. PubMed PMID: 26843822; PubMed Central PMCID: PMCPMC4703807.
  55. Nam SM, Choi JH, Choi SH, Cho HJ, Cho YJ, Rhim H, Kim HC, Cho IH, Kim DG, Nah SY. Ginseng gintonin alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis through lysophosphatidic acid 1 receptor. Epub 2021/05/25 J Ginseng Res 2021;45(3):390-400. https://doi.org/10.1016/j.jgr.2020.04.002. PubMed PMID: 34025132; PubMed Central PMCID: PMCPMC8134849.