An integrative study on the effects of Lingguizhugan decoction in treating Alzheimer's disease rats through modulation of multiple pathways involving various components

Abstract

Objective: To explore the active components and mechanisms of Lingguizhugan decoction (LGZGD) in the treatment of Alzheimer's disease (AD) through an integrated approach.

Methods: The active components of LGZGD in rat serum were identified using HPLC-FTICR MS. Network pharmacology and molecular docking analyses were conducted, and their findings were validated using an Aβ_1-42-induced AD rat model.

Results: Twenty-four active components and 324 common targets were identified and used to construct the networks. KEGG pathway enrichment analysis linked key target genes with MAPK, Rap1, and NF-κB signaling pathways. Molecular docking results indicated that three key targets (IL-6, TNF, and EGFR) and 10 core components are closely associated with LGZGD in the treatment of AD. LGZGD improved the spatial learning and memory abilities of AD rats. LGZGD reduced neuronal damage and increased the number of neurons in the cortex and hippocampal CA1 region of AD rats. LGZGD decreased Aβ_1-42 expression in the rat hippocampus, alleviated oxidative stress in AD rats, and decreased TNF-α, IL-6, IL-1β, and HMGB1 levels in the cerebral cortical tissue. LGZGD markedly decreased Iba-1 and iNOS expression and increased CD206 levels to inhibit M1 activation and promote M2 activation. LGZGD increased the expression of p-GSK-3β, ERK, and p-ERK, while decreasing the expression of p-Tau, IKKβ, p-IκBα, p-p65, p-p38, and p-JNK in the hippocampus of AD rats.

Conclusion: LGZGD treats AD by modulating targets like IL-6, TNF, MAPK3, and BCL2, thereby alleviating cognitive impairments in rats. Its neuroprotective effects in treating AD are mediated through the NF-κB/MAPK signaling pathways.

Keywords: Alzheimer's disease; In vivo validation; Lingguizhugan decoction; Molecular docking; NF-κB/MAPK signaling pathway; Network pharmacology.