Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors

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.

Cognitive improvement effect of gintonin might be associated with blood-brain barrier permeability enhancement: dynamic contrast-enhanced MRI pilot study

“…Previous studies have demonstrated the effect of gintonin on the BBB permeability based on the in vitro or the in vivo models [ 16 18 24 25 ]. In a study using human brain microvascular endothelial cells, gintonin induced widening of the junctional spaces, modulated the expression levels of the endothelial junctional proteins such as cadherin, occludin, zonula occludens 1, and claudin-5, and also enabled the entrance of large molecules to enter the cells [ 24 ].…”

“…In a study using human brain microvascular endothelial cells, gintonin induced widening of the junctional spaces, modulated the expression levels of the endothelial junctional proteins such as cadherin, occludin, zonula occludens 1, and claudin-5, and also enabled the entrance of large molecules to enter the cells [ 24 ]. In a rodent model, the fluorescent-labeled gintonin well distributed throughout the endothelium, neurons and glial cells after intravenous injection [ 18 ]. It is also found that the permeability enhancing effect of gintonin is mediated by its binding with the highly expressed LPA receptors in the cerebrovascular endothelium, the LPA 1/3, and secondary increment of VEGF [ 16 25 ].…”

“…As gintonin was also tolerable in the higher doses, future studies might include multiple dosage regimens with higher doses of GEF. As gintonin was safe without provoking adverse events, gintonin might have a potential clinical utility in the long-term management of the cognitive dysfunction, as a combination treatment added to the conventional treatment agents, for example, to determine the efficacy of the brain entrance of the co-administered donepezil [ 18 ].…”

“…In conclusion, we have demonstrated gintonin alters human BBB permeability in the major structures involving in the global cognitive function. It might potentially promote their clinical utility, as it can facilitate the delivery of other AD treatment agents into the brain, when used in combination [ 18 ].…”

“…High levels of LPA receptors are expressed in brain endothelial cells, and animal studies have shown that gintonin acts on LPA receptors to induce blood-brain barrier (BBB) opening [ 16 17 ]. Considering that the efficient delivery of drugs beyond the BBB into the brain parenchyma is a fundamental issue of drug treatment for central nervous system diseases, the permeability enhancing effect of gintonin is an important feature that can significantly increase the clinical efficacy [ 18 ].…”