Ginsenoside Rg2 alleviates astrocyte inflammation and ameliorates the permeability of the Alzheimer's disease related blood-brain barrier

Ya-Wei Lu; Ya-Jun Wang; Zi Wang; Shen Ren; Xiao-Jie Gong; Jun-Nan Hu; Jing-Tian Zhang; Wei Li

doi:10.1016/j.phymed.2024.156063

Ginsenoside Rg2 alleviates astrocyte inflammation and ameliorates the permeability of the Alzheimer's disease related blood-brain barrier

Phytomedicine. 2024 Sep 16:135:156063. doi: 10.1016/j.phymed.2024.156063. Online ahead of print.

Authors

Ya-Wei Lu¹, Ya-Jun Wang², Zi Wang¹, Shen Ren¹, Xiao-Jie Gong³, Jun-Nan Hu¹, Jing-Tian Zhang⁴, Wei Li⁵

Affiliations

¹ College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China.
² College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China; College of Life Sciences, Jilin Agricultural University, Changchun 130118, PR China.
³ Department of Biological Engineering, College of Life Science, Dalian Minzu University, Dalian 116600, PR China.
⁴ College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China. Electronic address: zjt18104440010@126.com.
⁵ College of Chinese Medicinal Materials, National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Jilin Agricultural University, Changchun 130118, PR China; College of Life Sciences, Jilin Agricultural University, Changchun 130118, PR China. Electronic address: liwei7727@126.com.

PMID: 39305744
DOI: 10.1016/j.phymed.2024.156063

Abstract

Background: Damage to the blood-brain barrier (BBB) is vital for the development of Alzheimer's disease (AD). Ginsenoside Rg2 (G-Rg2) has been shown to improve a variety of brain injuries, but whether G-Rg2 can improve the BBB leakage related to AD is still unclear.

Purpose: Illuminate the effect and mechanism of G-Rg2 on AD-related BBB damage. To clarify the role of G-Rg2 in Toll-like receptor pathway and oxidative stress pathway and its effect on tight junction proteins (TJs) expression in vivo and in vitro experiments.

Methods and results: In our research, the tightness of the BBB was improved and the inflammatory pathway was suppressed after 4 weeks of treatment with G-Rg2 (10 mg kg^-1 and 20 mg kg^-1) in aluminum trichloride (AlCl₃) plus d-galactose (D-gal) caused AD mice (p < 0.05; p < 0.01). Concurrently, the stability of TJs in mouse brain endothelial cells (bEnd3) was improved after okadaic acid (OA) -induced AD model cells were pretreated with G-Rg2 (5 μM, 10 μM, and 20 μM) for 24 h (p < 0.05; p < 0.01). The oxidative stress pathway and Toll-like receptor pathway in mouse astrocyte-cerebellum (MA-c) were inhibited (p < 0.05; p < 0.01). Meanwhile, in vitro interaction model results showed that G-Rg2 reduced the activation of MA-c, thereby alleviating the degradation of TJs in bEnd3 (p < 0.05; p < 0.01). The co-culture system of MA-c and bEnd3 further clearly demonstrated that G-Rg2 (20 μM) could improve their interaction and enhance BBB tightness.

Conclusion: This study suggests that G-Rg2 can inhibit the TLR4/MyD88/MMP9 inflammatory pathway by reducing the activation of MA-c and the binding of TLR4 to MyD88, thereby decreasing the secretion of inflammatory factors and matrix metalloproteinases (MMPs), hence maintaining the stability of TJs in bEnd3, which may be one of the mechanisms of G-Rg2 in reducing AD-related BBB damage.

Keywords: Astrocytes; Blood-brain barrier; Brain endothelial; Ginsenoside Rg2; Inflammation; Oxidative stress.