Dihuang-Yinzi Alleviates Cognition Deficits via Targeting Energy-Related Metabolism in an Alzheimer Mouse Model as Demonstrated by Integration of Metabolomics and Network Pharmacology

Abstract

Energy metabolism disturbance and the consequent reactive oxygen species (ROS) overproduction play a key and pathogenic role in the onset and progression of Alzheimer’s disease (AD). Dihuang-Yinzi (DHYZ) is a traditional Chinese herbal prescription clinically applied to treat AD and other neurodegenerative diseases for a long time. However, the systematical metabolic mechanism of DHYZ against AD remains largely unclear. Here we aimed to explore the mechanism of DHYZ in the treatment of AD comprehensively in an in vivo metabolic context by performing metabolomics analysis coupled with network pharmacology study and experimental validation. The network pharmacology was applied to dig out the potential target of DHYZ against AD. The metabolomics analysis based on UPLC-HRMS was carried out to profile the urine of 2× Tg-AD mice treated with DHYZ. By integrating network pharmacology and metabolomics, we found DHYZ could ameliorate 4 key energy-related metabolic pathways, including glycerophospholipid metabolism, nicotinate/nicotinamide metabolism, glycolysis, and tricarboxylic acid cycle. Besides, we identified 5 potential anti-AD targets of DHYZ, including DAO, HIF1A, PARP1, ALDH3B2, and ACHE, and 14 key differential metabolites involved in the 4 key energy-related metabolic pathways. Furthermore, DHYZ depressed the mitochondrial dysfunction and the resultant ROS overproduction through ameliorating glycerophospholipid metabolism disturbance. Thereby DHYZ increased nicotinamide adenine dinucleotide (NAD+) content and promoted glycolysis and tricarboxylic acid (TCA) cycle, and consequently improved oxidative phosphorylation and energy metabolism. In the present study, we provided a novel, comprehensive and systematic insight into investigating the therapeutic efficacy of DHYZ against AD via ameliorating energy-related metabolism.

Neuroprotective Mechanisms and Metabolomics Analysis of Jiedu Yizhi Formula in Alzheimer's Disease

“…The researchers conducted urinary metabolomics analysis of AD mice using UPLC-HRMS and identi ed that Rehmannia drink in uences four energy-related metabolic pathways, comprising glycerophospholipid metabolism, niacin/nicotinamide metabolism, glycation, and tricarboxylic acid cycle. They demonstrated that the disorder in glycerophospholipid metabolism is ameliorated by Rehmannia drink (Han et al 2022). The results of this study demonstrate that both Western medicine and traditional Chinese medicine have the potential to alleviate cognitive dysfunction in AD.…”

Effects of Xiaoyao San on exercise capacity and liver mitochondrial metabolomics in rat depression model

“…Lei et al systematically investigated the antidepressant effects of paeoniflorin on CUMS rats based on a combination of LC-MS metabolomics and network pharmacology analysis, and identified the citrate cycle as an important metabolic pathway, and SLC6A4, TNF, IL6, and SLC6A3 as key targets ( Lei et al, 2022 ). Han et al analyzed the urine of a mouse model of Alzheimer’s disease for metabolomics and combined it with network pharmacology, and found that Dihuang-Yinzi improved four energy-related metabolic pathways to alleviate cognitive deficits in AD disease, including glycerophospholipid metabolism, niacin/nicotinamide metabolism, glycolysis and the tricarboxylic acid cycle ( Han et al, 2022 ). Therefore, our study integrated network pharmacology and metabolomics and provided a new research strategy for the antidepressant effect of XYS.…”

Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

“…The traditional Chinese herbal prescription Dihuang-Yinzi has long been used to treat neurodegenerative diseases such as AD. Investigation into its mechanism of action revealed that the ability to increase NAD content and enhance energy metabolism may contribute to its neuroprotective activity [ 153 ].…”