Pharmacodynamics, Network Pharmacology, and Pharmacokinetics of Chinese Medicine Formula 9002A in the Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a common and serious neurodegenerative disease in the elderly; however, the treatment of AD is still lacking of rational drugs. In this paper, the active constituents and targets of the self-developed Chinese medicine Formula 9002A in the treatment of AD were investigated from three aspects: pharmacodynamics based on cell and animal experiments, network pharmacology analysis, and pharmacokinetic analysis. A total of 124 compounds were screened in Formula 9002A, and four constituents including salidroside, gastrodin, niacinamide, and umbelliferone were screened as potential active components for the treatment of AD by network pharmacology. Among them, salidroside and gastrodin showed higher relevance with AD targets, such as ESR1 and AR. The pharmacokinetic study showed that they could be absorbed and identified in plasma; the half-life and mean residence times of salidroside and gastrodin in plasma were nearly increased 2-fold by the administration of Formula 9002A compared with those by the administration of a monomer, indicating the extended action time of active compounds in vivo. Formula 9002A exerted the efficacy in the treatment of AD mainly by regulating APP, GSK3β, ESR1, and AR targets based on the anti-β-amyloid protein deposition, anti-oxidation and anti-apoptosis pathways. Two genes enriched in Alzheimer’s disease pathway, APP and GSK3β, were further validated. The experiments also demonstrated that Formula 9002A could downregulate APP and GSK3β protein expression in the model mice brain and improved their cognitive ability. In summary, Formula 9002A has the characteristics of multiple targets and multiple pathways in the treatment of AD, and salidroside and gastrodin might be the main active constituents, which could provide a foundation for further research and application.

Constituents, pharmacological activities, pharmacokinetic studies, clinical applications, and safety profile on the classical prescription Kaixinsan

“…Pharmacokinetics (PK) investigation mainly focuses on the changes in the process of medicine absorption, distribution, metabolism, and excretion (ADME) processes in vivo after oral administration, and provides a helpful approach to confirm the effective ingredients and guide the clinical usage of herbal medicine ( Tang et al, 2022 ). There are few investigations on the PK of whole KXS extracts.…”

Combining Artificial Intelligence with Traditional Chinese Medicine for Intelligent Health Management

“…Many attempts have been made to investigate the efficacy and mechanism of TCM with modern technology and methods; AI key technologies provide new means for evaluation and analysis. Machine learning algorithms have been used to construct a classifier to predict active molecules targeting 25 key targets of Alzheimer's disease and further study CHM for treating the disease [31]. A supervised classifier is trained by using the physicochemical properties of compounds obtained from high-throughput screening; their robustness is verified by various statistical parameters.…”

Brain Network Homeostasis and Plasticity of Salidroside for Achieving Neuroprotection and Treating Psychiatric Sequelae Stemming from Stress

“…but also protects against Aβ accumulation and Aβ-induced neurotoxicity(116,(140)(141)(142)(143)(144) by exerting anti-in ammatory and antioxidative effects, thus contributing to the amelioration of AD pathology.Both BACE1 and γ-secretase are required for the production of Aβ(99,134,145). Hypoxia can regulate secretase activity and expression and induce abnormal processing of amyloid precursor protein (APP) (116).…”

“…Salidroside can attenuate hypoxia-induced abnormal processing of Furthermore, salidroside can improve locomotor activity in a transgenic Drosophila model of AD, ameliorate Aβ-treated toxicity and reduce neuronal loss in the brain(140,141) by promoting phosphatidylinositide 3-kinase (PI3K)/Akt signalling(141). Salidroside increases the levels of phosphorylated glycogen synthase kinase 3β (p-GSK-3β), decreases the level of p-Tau(140,141), and regulates the APP and GSK-3β pathways(141,142) to protect against Aβ-induced neurotoxicity and alleviate AD and other neurodegenerative diseases (Fig.2).Salidroside alleviates Aβ-induced neurotoxicity and cell deathAβ oligomers, which are the principal toxic forms of Aβ, can cause cytotoxicity, mitochondrial damage, neurite degeneration and cell death in the brain(137)(138)(139), resulting in memory and learning impairment, cognitive decline and progression of AD(147, 148). Due to its potent pharmacological activities, salidroside can protect against Aβ-induced neurotoxicity and cell apoptosis or death in AD models and Aβ-treated cells(116,(140)(141)(142)(143)(144).…”