Protective Effects of Red Ginseng Against Tacrine-Induced Hepatotoxicity: An Integrated Approach with Network Pharmacology and Experimental Validation

Abstract

Introduction

Tacrine, an FDA-approved acetylcholinesterase inhibitor, has shown efficacy in treating Alzheimer’s disease, but its clinical use is limited by hepatotoxicity. This study investigates the protective effects of red ginseng against tacrine-induced hepatotoxicity, focusing on oxidative stress.

Methods

A network depicting the interaction between compounds and targets was constructed for RG. Effect of RG was determined by MTT and FACS analysis with cells stained by rhodamine 123. Proteins were extracted and subjected to immunoblotting for apoptosis-related proteins.

Results

The outcomes of the network analysis revealed a significant association, with 20 out of 82 identified primary RG targets aligning with those involved in oxidative liver damage including notable interactions within the AMPK pathway. in vitro experiments showed that RG, particularly at 1000μg/mL, mitigated tacrine-induced apoptosis and mitochondrial damage, while activating the LKB1-mediated AMPK pathway and Hippo-Yap signaling. In mice, RG also protected the liver injury induced by tacrine, as similar protective effects to silymarin, a well-known drug for liver toxicity protection.

Discussion

Our study reveals the potential of RG in mitigating tacrine-induced hepatotoxicity, suggesting the administration of natural products like RG to reduce toxicity in Alzheimer’s disease treatment.

Keywords:

• AMPK
• liver toxicity
• oxidative stress
• red ginseng
• tacrine

Abbreviations

ANOVA, one-way analysis of variance; CTI, compound-target interactions; DMEM, Dulbecco’s modified Eagle’s medium; DMSO, Dimethyl sulfoxide; FACS, Fluorescence-activated cell sorting; FBS, fetal bovine serum; KEGG, Kyoto Encyclopedia of Genes and Genomes; LATS1, phospho-large tumor suppressor; LKB1, phospho-liver kinase B1; OMIM, Online Mendelian Inheritance in Man; PI, propidium iodide; RG, Red ginseng; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Ethics Approval and Consent to Participate

The animal experimentation procedures of this study were approved and monitored by the Institutional Animal Care and Use Committee of Daegu Haany University (Number: DHU-2022-062).

Acknowledgments

Kim BJ would like to thank to the Ph.D.’s program of Dongguk University for completing the thesis through this work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was also supported by National Research Foundation (NRF) grant funded by the Korean government (No. 2022R1A2C1092168).