Efficacy and Mechanism of Fructus Water Extract in Alzheimer's Disease: Insights from Network Pharmacology and Validation in an Amyloid-β Infused Animal Model.

Background/objectives: Fructus (SCF) is a traditional medicinal herb containing lignans that improves glucose metabolism by mitigating insulin resistance. We aimed to investigate the therapeutic potential and action mechanism of SCF for Alzheimer's disease (AD) using a network pharmacology analysis, followed by experimental validation in an AD rat model.

Methods: The biological activities of SCF's bioactive compounds were assessed through a network pharmacology analysis. An AD rat model was generated by infusing amyloid-β peptide (Aβ) (25-35) into the hippocampus to induce Aβ accumulation. The AD rats were fed either 0.5% dextrin (AD-Con) or 0.5% SCF (AD-SCF group) in a high-fat diet for seven weeks. The rats in the normal/control group received an Aβ (35-25) infusion (no Aβ deposition) and were fed a control diet (Normal-C). Aβ deposition, memory function, inflammation, and glucose/lipid metabolism were evaluated.

Results: The network analysis revealed significant intersections between AD-related targets and bioactive SCF compounds, like gomisin A, schisandrin, and longikaurin A. Key AD genes prostaglandin-endoperoxide synthase-2 (, cyclooxygenase-2) and acetylcholinesterase () were linked to SCF compounds. In the rats with AD induced by bilaterally infusing amyloid-β (25-35) into the hippocampus, the 0.5% SCF intake mitigated hippocampal amyloid-β deposition, neuroinflammation, memory deficits, and dysregulated glucose and lipid metabolism versus the AD controls. SCF reduced hippocampal AChE activity, inflammatory cytokine expression related to , and malondialdehyde contents and preserved neuronal cell survival-related factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor similar to normal rats. The neuroprotective effects validated the network analysis findings.

Conclusions: SCF could be a potential AD therapeutic agent by activating the parasympathetic nervous system to reduce hippocampal oxidative stress and inflammation, warranting further clinical investigations of its efficacy.