Gintonin-mediated release of astrocytic vascular endothelial growth factor protects cortical astrocytes from hypoxia-induced cell damages

Choi, Sun-Hye; Kim, Hyeonjoong; Cho, Hee-Jung; Park, Sang-Deuk; Lee, Na-Eun; Hwang, Sung‐Hee; Rhim, Hyewon; Kim, Hyoung‐Chun; Cho, Ik‐Hyun; Nah, Seung‐Yeol

doi:10.1016/j.jgr.2018.05.006

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…The authors indicated that gintonin markedly regulated amyloid-β-induced cholinergic impairment, e.g., through reduced acetylcholine level and diminished ChAT activity, and increased the level of AChE [ 28 ]. Moreover, it was shown that gintonin regulates the expression of VEGF in astrocytes, which might provide protection against hypoxic injury [ 76 ]. It has been suggested that gintonin is able to protect mouse brain against methylmercury-induced neurotoxicity and learning processes [ 77 ].…”

Section: Effects Of Gintonin Against Different Models Of Neurodegmentioning

confidence: 99%

Ongoing Research on the Role of Gintonin in the Management of Neurodegenerative Disorders

Ikram

Ullah

Khan

et al. 2020

Cells

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Neurodegenerative disorders, namely Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD), and multiple sclerosis (MS), are increasingly major health concerns due to the increasingly aged population worldwide. These conditions often share the same underlying pathological mechanisms, including elevated oxidative stress, neuroinflammation, and the aggregation of proteins. Several studies have highlighted the potential to diminish the clinical outcomes of these disorders via the administration of herbal compounds, among which gintonin, a derivative of ginseng, has shown promising results. Gintonin is a noncarbohydrate/saponin that has been characterized as a lysophosphatidic acid receptor (LPA Receptor) ligand. Gintonin may cause a significant elevation in calcium levels [Ca2+]i intracellularly, which promotes calcium-mediated cellular effects via the modulation of ion channels and cell surface receptors, regulating the inflammatory effects. Years of research have suggested that gintonin has antioxidant and anti-inflammatory effects against different models of neurodegeneration, and these effects may be employed to tackle the neurological changes. Therefore, we collected the main scientific findings and comprehensively presented them, covering preparation, absorption, and receptor-mediated functions, including effects against Alzheimer’s disease models, Parkinson’s disease models, anxiety and depression-like models, and other neurological disorders, aiming to provide some insights for the possible usage of gintonin in the management of neurodegenerative conditions.

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Section: Effects Of Gintonin Against Different Models Of Neurodegmentioning

confidence: 99%

Ongoing Research on the Role of Gintonin in the Management of Neurodegenerative Disorders

Ikram

Ullah

Khan

et al. 2020

Cells

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“…5 A, coadministration of Ki16425 with gintonin + DPZ abolished gintonin-mediated enhancement of brain delivery of DPZ, indicating that gintonin-mediated enhancement of brain delivery of DPZ is achieved via LPA1/3 receptors. In previous reports, we showed that gintonin stimulates VEGF release in human umbilical vessel endothelial cells and astrocytes [ 16 , 17 ]. Furthermore, it was reported that VEGF is a kind of BBB opening agent [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

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

Choi

Lee

Cho

et al. 2021

Journal of Ginseng Research

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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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“… 3 We further showed that in vitro gintonin-mediated cellular effects via LPA receptors are coupled to beneficial effects in animal models of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). 8 , 10 , 17 , 18 Although previous in vitro and in vivo studies demonstrated GEF-mediated actions on normal brain and neurodegenerative diseases after oral administration, the effects of GEF on a broad spectrum of genetic expressions in animal brain, especially in the hippocampus was not fully understood. In the present study, we used NGS analysis (RNA-seq) to elucidate GEF-mediated gene expression regulations.…”

Section: Discussionmentioning

confidence: 99%

“… 8 In in vivo studies, gintonin-mediated activation of LPA-LPA receptor axis induces many beneficial brain functions; the increased hippocampal synaptic transmission and long-term potentiation (LTP), brain-derived neurotrophic factor (BDNF) expression, attenuation of hippocampal aging, enhancement of hippocampal dependent-cognitive functions, and finally prevention and attenuation of neurodegenerative diseases. 9 , 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

Effects of gintonin-enriched fraction on hippocampal gene expressions

Lee

Choi

et al. 2021

Integrative Medicine Research

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Background Recently, gintonin and gintonin-enriched fraction (GEF) have been isolated from ginseng, a herbal medicine. Gintonin induces [Ca 2+ ] i transition in cultured hippocampal neurons and stimulates acetylcholine release through LPA receptor activation. Oral administration of GEF is linked to hippocampus-dependent cognitive enhancement and other neuroprotective effects; however, effects of its long-term administration on hippocampal gene expression remains unknown. Here, we used next-generation sequence (NGS) analysis to examine changes in hippocampal gene expressions after long-term oral administration of GEF. Methods C57BL/6 mice were divided into three groups: control group, GEF50 (GEF 50 mg/kg, p.o. ), and GEF100 (GEF 100 mg/kg, p.o. ). After 22 days, total RNA was extracted from mouse hippocampal tissues. NGS was used for gene expression profiling; quantitative-real-time PCR and western blot were performed to quantify the changes in specific genes and to confirm the protein expression levels in treatment groups. Results NGS analysis screened a total of 23,282 genes, analyzing 11-related categories. We focused on the neurogenesis category, which includes four genes for candidate markers: choline acetyltransferase (ChAT) gene, β 3 -adrenergic receptor (Adrb3) gene, and corticotrophin-releasing hormone (Crh) gene, and tryptophan 2,3-dioxygenase (Tdo2) gene. Real-time PCR showed a marked overexpression of ChAT, Adrb3, and Crh genes, while reduced expression of Tdo2. Western blot analysis also confirmed increased ChAT and decreased Tdo2 protein levels. Conclusion We found that GEF affects mouse hippocampal gene expressions, associated with memory, cognitive, anti-stress and anti-anxiety functions, and neurodegeneration at differential degree, that might explain the genetic bases of GEF-mediated neuroprotective effects.

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Gintonin-mediated release of astrocytic vascular endothelial growth factor protects cortical astrocytes from hypoxia-induced cell damages

Cited by 12 publications

References 32 publications

Ongoing Research on the Role of Gintonin in the Management of Neurodegenerative Disorders

Ongoing Research on the Role of Gintonin in the Management of Neurodegenerative Disorders

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

Effects of gintonin-enriched fraction on hippocampal gene expressions

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