Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors

  • Choi, Sun-Hye (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University) ;
  • Lee, Na-Eun (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) ;
  • Lee, Ra Mi (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) ;
  • Han, Mun (Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Lee, Eun-Hee (Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Park, Juyoung (Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Kim, Jeong Nam (Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine) ;
  • Kim, Byung Joo (Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine) ;
  • Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
  • Received : 2019.09.02
  • Accepted : 2019.12.04
  • Published : 2021.03.01
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Abstract

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

Keywords

Acknowledgement

This study was supported by the Brain Research Program through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science, Information & Communication Technology (ICT), and Future Planning (NRF-2016M3C7A1913845, NRF-2016M3C7A1913933). S-.Y.N. received funding from the Basic Science Research Program (NRF-2017R1D1A1A09000520). This present study was supported by Korean National Research Foundation (NRF) grant funded by the Korean Government (MSIP) (Grant no. 2014R1A5A2009936).

References

  1. Meng G, Zhong X, Mei H. A systematic investigation into aging related genes in brain and their relationship with Alzheimer's disease. PLoS One 2016;11:e0150624. https://doi.org/10.1371/journal.pone.0150624
  2. Peters R. Ageing and the brain. Postgrad Med J 2006;82:84-8. https://doi.org/10.1136/pgmj.2005.036665
  3. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013;11:315-35. https://doi.org/10.2174/1570159X11311030006
  4. Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Moller HJ, et al. The effects of donepezil in Alzheimer's disease - results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237-44. https://doi.org/10.1159/000017126
  5. Jelic V, Darreh-Shori T. Donepezil: a review of pharmacological characteristics and role in the management of Alzheimer disease. Clin Med Insights Ther 2010;2:771-88.
  6. Nuri TH, Yee JC, Gupta M, Khan M, Ming LC. A review of Panax ginseng as an herbal medicine. Arch Pharma Pract 2016;7:61-5. https://doi.org/10.4103/2045-080X.183030
  7. 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
  8. Choi SH, Jung SW, Lee BH, Kim HJ, Hwang SH, Kim HK, 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
  9. Nah SY. Gintonin: a novel ginseng-derived ligand that targets G protein-coupled lysophosphatidic acid receptors. Curr Drug Targets 2012;13:1659-64. https://doi.org/10.2174/138945012803529947
  10. 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
  11. Pyo MK, Choi SH, Hwang SH, Shin TJ, Lee BH, Lee SM, Lim YH, Kim DH, Nah SY. Novel glycolipoproteins from ginseng. J Ginseng Res 2011;35:92-103. https://doi.org/10.5142/jgr.2011.35.1.092
  12. Liu L, Duff K. A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse. J Vis Exp 2008;10:960.
  13. Cho HJ, Choi SH, Kim HJ, Lee BH, Rhim H, Kim HC, Hwang SH, Nah SY. Bioactive lipids in gintonin-enriched fraction from ginseng. J Ginseng Res 2019;43:209-17. https://doi.org/10.1016/j.jgr.2017.11.006
  14. Kim DG, Jang M, Choi SH, Kim HJ, Jhun H, Kim HC, Rhim H, Cho IH, Nah SY. Gintonin, a ginseng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery. Int J Biol Macromol 2018;15:1325-37.
  15. Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J, et al. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol 2003;64:994-1005. https://doi.org/10.1124/mol.64.4.994
  16. Hwang SH, Lee BH, Choi SH, Kim HJ, Won KJ, Lee HM, Rhim H, Kim HC, Nah SY. Effects of gintonin on the proliferation, migration, and tube formation of human umbilical-vein endothelial cells: involvement of lysophosphatidic-acid receptors and vascular-endothelial-growth-factor signaling. J Ginseng Res 2016;40:325-33. https://doi.org/10.1016/j.jgr.2015.10.002
  17. Choi SH, Kim HJ, Cho HJ, Park SD, Lee NE, Hwang SH, Rhim H, Kim HC, Cho IH, Nah SY. Gintonin-mediated release of astrocytic vascular endothelial growth factor protects cortical astrocytes from hypoxia-induced cell damages. J Ginseng Res 2019;43:305-11. https://doi.org/10.1016/j.jgr.2018.05.006
  18. Jiang S, Xia R, Jiang Y, Wang L, Gao F. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier. PLoS One 2014;9:e86407. https://doi.org/10.1371/journal.pone.0086407
  19. Hawkins BT, Sykes DB, Miller DS. Rapid, reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor. J Neurosci 2010;30:1417-25. https://doi.org/10.1523/JNEUROSCI.5103-09.2010
  20. Tonda-Turo C, Origlia N, Mattu C, et al. Current limitations in the treatment Parkinson's and Alzheimer's diseases: state-of-the-art and future perspective of polymeric carriers. Curr Med Chem 2018;25:5755-71. https://doi.org/10.2174/0929867325666180221125759
  21. Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care 2014;3:647-61. https://doi.org/10.1089/wound.2013.0517
  22. Jackson S, Ham RJ, Wilkinson D. The safety and tolerability of donepezil in patients with Alzheimer's disease. Br J Clin Pharmacol 2004;58:1-8. https://doi.org/10.1111/j.1365-2125.2004.01848.x

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