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Background A dramatic increase in aging populations and low birth rates rapidly drive aging societies and increase aging-associated neurodegenerative diseases. However, functional food or medicinal formulations to prevent geriatric brain disorders are not readily available. Panax ginseng is a candidate, since ginseng has long-been consumed as a rejuvenating agent. However, the underlying molecular mechanisms and the components of ginseng that are responsible for brain rejuvenation and human longevity are unknown. Accumulating evidence shows that gintonin is a candidate for the anti-aging ingredient of ginseng, especially in brain senescence. Methods Gintonin, a glycolipoprotein complex, contains three lipid-derived G protein-coupled receptor ligands: lysophosphatidic acids (LPAs), lysophosphatidylinositols (LPIs), and linoleic acid (LA). LPA, LPI, and LA act on six LPA receptor subtypes, GPR55, and GPR40, respectively. These G protein-coupled receptors are distributed within the nervous and non-nervous systems of the human body. Results Gintonin-enriched fraction (GEF) exhibits anti-brain senescence and effects against disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Oral administration of gintonin in animal models of d -galactose-induced brain aging, AD, HD, and PD restored cognitive and motor functions. The underlying molecular mechanisms of gintonin-mediated anti-brain aging and anti-neurodegenerative diseases include neurogenesis, autophagy stimulation, anti-apoptosis, anti-oxidative stress, and anti-inflammatory activities. This review describes the characteristics of gintonin and GEF, and how gintonin exerts its effects on brain aging and brain associated-neurodegenerative diseases. Conclusion Finally, we describe how GEF can be applied to improve the quality of life of senior citizens in aging societies.

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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.

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It has been previously indicated that gintonin, which is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand, restores memory dysfunctions in an APPswe/PSEN-1 double-transgenic mouse model of Alzheimer's disease (AD Tg mice) by attenuating β-amyloid plaque deposition, recovering cholinergic dysfunctions and upregulating hippocampal neurogenesis in the cortex and hippocampus. Although β-amyloid plaque depositions in AD is accompanied with disruptions of brain microvessels, including the brain-blood barrier (BBB), it is unknown whether gintonin exerts protective effects on brain microvascular dysfunctions in AD Tg mice. In the present study, the effects of gintonin-enriched fraction (GEF) on the changes in β-amyloid plaque depositions, brain permeability of Evans blue, and microvascular junctional proteins were investigated in AD Tg mice. Long-term oral administration of GEF reduced β-amyloid plaque depositions in the cortex and hippocampus of AD Tg mice. GEF treatment also reduced the permeability of Evans blue through BBB and decreased immunoreactivity of platelet endothelial cell adhesion molecule-1 (a marker of BBB disruption) in the cortex and hippocampus of AD Tg mice in a dose-dependent manner. However, GEF elevated the protein expression of occludin, claudin-5 and zonula occludens-1, which are tight-junction proteins. The present results demonstrated that long-term oral GEF treatment not only attenuates β-amyloid plaque depositions in the brain but also exhibits protective effects against microvascular disruptions in AD Tg mice. Finally, GEF exhibits anti-AD effects through attenuation of β-amyloid plaque depositions and protection against brain microvascular damage in an AD animal model.