Ginsenoside Rg1 Prevents Cognitive Impairment and Hippocampal Neuronal Apoptosis in Experimental Vascular Dementia Mice by Promoting GPR30 Expression

Abstract

This study is aimed at investigating the potential roles of G protein-coupled estrogen receptor 1 (GPER, also known as GPR30) in the preventive effect of ginsenoside Rg1 against cognitive impairment and hippocampal cell apoptosis in experimental vascular dementia (VD) in mice. The effects of bilateral common carotid artery stenosis (BCAS) on GPR30 expression at mRNA level were evaluated. Thereafter, the BCAS mouse model was utilized to evaluate the protection of Rg1 (0.1, 1, 10 mg/kg, 14 days, ip). Spatial memory was evaluated by water Morris Maze 7 days post BCAS. After behavioral tests, neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and potential mechanisms were determined using western blotting and quantitative real-time PCR. Our results showed that GPR30 expression in the hippocampal region at mRNA level was promoted 30 min, 3 h, 6 h, and 24 h following BCAS. Ginsenoside Rg1 (1 or 10 mg/kg, 14 days, ip) promoted GPR30 expression in the hippocampus of model mice (after behavioral tests) but did not alter GPR30 expression in the hippocampus of control mice. Moreover, treatment of ginsenoside Rg1 (10 mg/kg) or G1 (5 μg/kg), a GPR30 agonist, prevented BCAS-induced memory impairment and hippocampal neuronal loss and apoptosis and promoted the ratio of Bcl-2 to Bax expression in the hippocampus (after behavioral tests). On the contrary, G15 (185 μg/kg), an antagonist of GPR30, aggravated BCAS-induced hippocampal neuronal loss and apoptosis. Finally, drug-target molecular docking pointed that Rg1 had a lower binding energy with GPR30 compared with Bax and Bcl-2. Together, our data implicate that ginsenoside Rg1 prevents cognitive impairment and hippocampal neuronal apoptosis in VD mice, likely through promoting GPR30 expression. These results would provide important implications for the application of Rg1 in the treatment of VD.

G-Protein-Coupled Estrogen Receptor Expression in Rat Uterine Artery Is Increased by Pregnancy and Induces Dilation in a Ca2+ and ERK1/2 Dependent Manner

“…The following supporting information can be downloaded at: . References [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ] are cited in Supplementary Materials.…”

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

“…Although the majority of estrogen-induced neuroprotection has been attributed to classical nuclear ERs, there is growing evidence for the neuroprotective potential of nonnuclear ERs. Initially, researchers focused on GPER1, which became a main focus in studying the neuroprotective capacity of phytoestrogens (e.g., ginsenoside Rg1), flavonoids (geinstein, daidzein), and synthetic SERMs (e.g., STX) [ 1 , 2 , 11 , 72 ]. Selective activation of GPER1 appeared to cause neuroprotection in animal models of mood disorders, Alzheimer’s disease, and Parkinson’s disease, but there is no consensus on the role played by GPER1 in ischemic stroke [ 73 ].…”

“…It has been shown that treatment with G1 protects against traumatic brain injury, which is considered a risk factor for Alzheimer’s disease, and improves early-onset cognitive impairment in rats via the PI3K/Akt pathway [ 111 ]. Similarly, GPER1 activation inhibited oxidative stress, neuroinflammation, and apoptosis, improving memory and cognitive dysfunctions in a mouse model of Alzheimer’s disease (5XFAD), a mouse model of vascular dementia, and a mouse model of 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) [ 68 , 72 , 112 ]. Evidence has shown that a decrease in GPER1 expression impairs learning and memory, which involves actin depolymerization and the SRC-1 and PI3K/mTORC2 pathways [ 113 ].…”

Acupoint catgut embedding improves learning and memory impairment in vascular dementia rats

“…TLRs are receptors that mainly recognize pathogenic microorganisms in the natural immune system. When cerebral ischemia occurs, TLRs are activated, sending signals to trigger inflammatory reactions, and an abundance proinflammatory cytokines and adhesion factors are expressed, leading to brain tissue damage (27)(28)(29). There are many classifications of TLRs, among which TLR4 distributed on the cell surface can be expressed by vascular smooth muscle cells and endothelial cells in the brain, which can stimulate the secretion of inflammatory substances, and participate in and mediate inflammatory injury (30,31).…”