Choi, Sun-Hye Lee, Na-Eun Cho, Hee-Jung Lee, Ra Mi Rhim, Hyewhon Kim, Hyoung-Chun Han, Mun Lee, Eun-Hee Park, Juyoung Nah, Seung-Yeol 2024-01-19T15:05:34Z 2024-01-19T15:05:34Z 2021-09-05 2021-03 1226-8453 https://pubs.kist.re.kr/handle/201004/117338 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) thorn 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. (C) 2020 The Korean Society of Ginseng, Published by Elsevier Korea LLC. English 고려인삼학회 Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors Article 10.1016/j.jgr.2019.12.002 1 Journal of Ginseng Research, v.45, no.2, pp.264 - 272 Journal of Ginseng Research 45 2 264 272 Y scie scopus kci ART002721661 000632821600008 2-s2.0-85077712500 Plant Sciences Chemistry, Medicinal Integrative & Complementary Medicine Plant Sciences Pharmacology & Pharmacy Integrative & Complementary Medicine Article Alzheimer disease Brain delivery Donepezil Ginseng Gintonin