DOI QR코드

DOI QR Code

Cognitive function improvement effects of gintonin-enriched fraction in subjective memory impairment: An assessor- and participant-blinded placebo-controlled study

  • Rami Lee (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Han Sang Lee (Department of Neurology, Seoul National University Hospital) ;
  • Won-Woo Kim (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Manho Kim (Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Seung-Yeol Nah (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
  • 투고 : 2023.04.26
  • 심사 : 2023.06.14
  • 발행 : 2023.11.01

초록

Background: Gintonin is a new material of ginseng that acts through the ginseng-derived lysophosphatidic acid (LPA) receptor ligand. The gintonin-enriched fraction (GEF) inhibits amyloid plaque accumulation in the cortex and hippocampus, improves cognitive dysfunction by increasing acetylcholine levels, and promoted hippocampal neurogenesis in an animal model of Alzheimer's disease. We evaluated the effect of the GEF on the cognitive performance of subjects with subjective memory impairment (SMI). Methods: In this eight-week, randomized, assessor- and participant-blinded, placebo-controlled study, participants with SMI were assigned to three groups receiving placebo, GEF 300 mg/day or GEF 600 mg/day. The Korean versions of the Alzheimer's Disease Assessment Scale (K-ADAS), Mini-Mental State Examination (K-MMSE), and Stroop color-word test (K-SCWT) were also evaluated along with the safety profiles. Results: One hundred thirty-six participants completed the study. After eight weeks, we analyzed intergroup differences in primary or secondary outcome score changes. When we compared the GEF group with the placebo group, we observed significant improvements in the K-ADAS and K-SCWT scores. The GEF group did not show a significant improvement in K-MMSE and BDI scores compared to the placebo group. No adverse events were observed in the gintonin and placebo groups for eight weeks. Conclusion: The GEF is safe and effective in improving subjective cognitive impairment related to both the K-ADAS and K-SCWT in this study. However, further large-scale and randomized controlled studies are warranted to secure other cognitive function tests besides the K-ADAS and K-SCWT, and to confirm the findings of the current study.

키워드

과제정보

This work was supported by a grant from the Ministry of Health and Welfare (HU22C0168) to M. Kim and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2023R1A2C1003481) to S.Y. Nah.

참고문헌

  1. 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(2):151-62. https://doi.org/10.1007/s10059-012-2216-z. 
  2. 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. https://doi.org/10.3389/fphar.2015.00245. 
  3. Kim HJ, Shin EJ, Lee BH, Choi SH, Jung SW, Cho IH, Hwang SH, Kim JY, Han JS, Chung C, et al. Oral administration of gintonin attenuates cholinergic impairments by scopolamine, amyloid-beta protein, and mouse model of Alzheimer's disease. Mol Cells 2015;38(9):796-805. https://doi.org/10.14348/molcells.2015.0116. 
  4. 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 Alzheimers Dis 2012;31(1):207-23. https://doi.org/10.3233/JAD-2012-120439. 
  5. 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. 
  6. 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(1):55-61. https://doi.org/10.1016/j.jgr.2015.05.001. 
  7. Shin TJ, Kim HJ, Kwon BJ, Choi SH, Kim HB, Hwang SH, Lee BH, Lee SM, Zukin RS, Park JH, et al. Gintonin, a ginseng-derived novel ingredient, evokes long-term potentiation through n-methyl-d-aspartic acid receptor activation: involvement of lpa receptors. Mol Cells 2012;34(6):563-72. https://doi.org/10.1007/s10059-012-0254-4. 
  8. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013;9(1):63-75 e2. https://doi.org/10.1016/j.jalz.2012.11.007. 
  9. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack Jr CR, Kaye J, Montine TJ, et al. Toward defining the preclinical stages of alzheimer's disease: recommendations from the national institute on aging-alzheimer's association workgroups on diagnostic guidelines for alzheimer's disease. Alzheimers Dement 2011;7(3):280-92. https://doi.org/10.1016/j.jalz.2011.03.003. 
  10. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, et al. Dementia prevention, intervention, and care: 2020 report of the lancet commission. Lancet 2020;396(10248):413-46. https://doi.org/10.1016/S0140-6736(20)30367-6. 
  11. Weimer DL, Sager MA. Early identification and treatment of alzheimer's disease: social and fiscal outcomes. Alzheimers Dement 2009;5(3):215-26. https://doi.org/10.1016/j.jalz.2009.01.028. 
  12. Jessen F, Wolfsgruber S, Wiese B, Bickel H, Mosch E, Kaduszkiewicz H, Pentzek M, Riedel-Heller SG, Luck T, Fuchs A, et al. Ad dementia risk in late mci, in early mci, and in subjective memory impairment. Alzheimers Dement 2014;10(1):76-83. https://doi.org/10.1016/j.jalz.2012.09.017. 
  13. Jessen F, Wiese B, Bachmann C, Eifflaender-Gorfer S, Haller F, Kolsch H, Luck T, Mosch E, van den Bussche H, Wagner M, et al. Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry 2010;67(4):414-22. https://doi.org/10.1001/archgenpsychiatry.2010.30. 
  14. Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database Syst Rev 2006;3:CD006104. https://doi.org/10.1002/14651858.CD006104. 
  15. Doody RS, Ferris SH, Salloway S, Sun Y, Goldman R, Watkins WE, Xu Y, Murthy AK. Donepezil treatment of patients with mci: a 48-week randomized, placebo-controlled trial. Neurology 2009;72(18):1555-61. https://doi.org/10.1212/01.wnl.0000344650.95823.03. 
  16. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, et al. Effect of rivastigmine on delay to diagnosis of alzheimer's disease from mild cognitive impairment: the inddex study. Lancet Neurol 2007;6(6):501-12. https://doi.org/10.1016/S1474-4422(07)70109-6. 
  17. Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, Fraser G, Kesler S, Levin SM, Lucey B, et al. Dietary and lifestyle guidelines for the prevention of alzheimer's disease. Neurobiol Aging 2014;35(Suppl 2):S74-8. https://doi.org/10.1016/j.neurobiolaging.2014.03.033. 
  18. Lee WJ, Shin YW, Chang H, Shin HR, Kim WW, Jung SW, Kim M, Nah SY. Safety and efficacy of dietary supplement (gintonin-enriched fraction from ginseng) in subjective memory impairment: a randomized placebo-controlled trial. Integr Med Res 2022;11(1):100773. https://doi.org/10.1016/j.imr.2021.100773. 
  19. Lee WJ, Shin YW, Kim DE, Kweon MH, Kim M. Effect of desalted salicornia europaea l. Ethanol extract (pm-ee) on the subjects complaining memory dysfunction without dementia: a 12 week, randomized, double-blind, placebo-controlled clinical trial. Sci Rep 2020;10(1):19914. https://doi.org/10.1038/s41598-020-76938-x. 
  20. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7(2):27-31. https://doi.org/10.4103/0976-0105.177703. 
  21. Kang Yn DL, Hahn S. A validity study on the Korean mini-mental state examination (k-mmse) in dementia patients. J Korean Neurol Assoc 1997;15(2):300-8. 
  22. Youn JC, Lee DY, Kim KW, Lee JH, Jhoo JH, Lee KU, Ha J, Woo JI. Development of the Korean version of alzheimer's disease assessment scale (adas-k). Int J Geriatr Psychiatry 2002;17(9):797-803. https://doi.org/10.1002/gps.699. 
  23. Kim Ty Kss JE, Lee EA, Yoo BG, Lee SC, Hong TY, Kim MJ. Development of the Korean stroop test and study of the validity and the reliability. J Korean Geriatr Soc 2004;8(4):233-40. 
  24. Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (meddra). Drug Safety 1999;20(2):109-17. https://doi.org/10.2165/00002018-199920020-00002. 
  25. Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S. Donepezil 401 Study G. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004;63(4):651-7. https://doi.org/10.1212/01.wnl.0000134664.80320.92. 
  26. Rosen WG, Mohs RC, Davis KL. A new rating scale for alzheimer's disease. Am J Psychiatry 1984;141(11):1356-64. https://doi.org/10.1176/ajp.141.11.1356. 
  27. Kim HJ, Jung SW, Kim SY, Cho IH, Kim HC, Rhim H, Kim M, Nah SY. Panax ginseng as an adjuvant treatment for alzheimer's disease. J Gin Res 2018;42(4):401-11. https://doi.org/10.1016/j.jgr.2017.12.008. 
  28. Dong L, May BH, Feng M, Hyde AJ, Tan HY, Guo X, Zhang AL, Lu C, Xue CC. Chinese herbal medicine for mild cognitive impairment: a systematic review and meta-analysis of cognitive outcomes. Phytother Res 2016;30(10):1592-604. https://doi.org/10.1002/ptr.5679. 
  29. Maruyama M, Tomita N, Iwasaki K, Ootsuki M, Matsui T, Nemoto M, Okamura N, Higuchi M, Tsutsui M, Suzuki T, et al. Benefits of combining donepezil plus traditional Japanese herbal medicine on cognition and brain perfusion in alzheimer's disease: a 12-week observer-blind, donepezil monotherapy controlled trial. J Am Geriatr Soc 2006;54(5):869-71. https://doi.org/10.1111/j.1532-5415.2006.00722.x. 
  30. Shi J, Ni J, Lu T, Zhang X, Wei M, Li T, Liu W, Wang Y, Shi Y, Tian J. Adding Chinese herbal medicine to conventional therapy brings cognitive benefits to patients with alzheimer's disease: a retrospective analysis. BMC Complement Altern Med 2017;17(1):533. https://doi.org/10.1186/s12906-017-2040-5. 
  31. Zhao J, Li K, Wang Y, Li D, Wang Q, Xie S, Wang J, Zuo Z. Enhanced anti-amnestic effect of donepezil by ginkgo biloba extract (egb 761) via further improvement in pro-cholinergic and antioxidative activities. J Ethnopharmacol 2021;269:113711. https://doi.org/10.1016/j.jep.2020.113711. 
  32. Liu H, Ye M, Guo H. An updated review of randomized clinical trials testing the improvement of cognitive function of ginkgo biloba extract in healthy people and alzheimer's patients. Front Pharmacol 2019;10:1688. https://doi.org/10.3389/fphar.2019.01688. 
  33. 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 Jan-Mar;32(1):85-7. https://doi.org/10.1097/WAD.0000000000000213. PMID: 29028648. 
  34. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, et al. Vitamin e and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352(23):2379-88. https://doi.org/10.1056/NEJMoa050151. 
  35. Sheen YS, Huang HY, Liao YH. The efficacy and safety of an antiaging topical serum containing hesperetin and sodium cyclic lysophosphatidic acid: a single-center clinical trial. J Cosmet Dermatol 2021;20(12):3960-7. https://doi.org/10.1111/jocd.14063. 
  36. Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, Chen MH, Hemmelgarn B, Straus SE. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ 2013;185(16):1393-401. https://doi.org/10.1503/cmaj.130451. 
  37. Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, Truyen L, Mayorga AJ, Wang D, Brashear HR, Nye JS, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008;70(22):2024-35. https://doi.org/10.1212/01.wnl.0000303815.69777.26.