Astragaloside IV ameliorates cognitive impairment in heart failure rats via modulation of RAGE‐ERK1/2‐NF‐ κ B signalling pathway

BACKGROUND AND PURPOSE: Cognitive impairment (CI) is prevalent in clinical patients with heart failure (HF). However, there are no effective pharmacological interventions for CI treatment. Astragaloside IV (AS-IV) is the principal constituent of Astragalus Radix and effective in HF, but its action on CI after HF has not yet been studied. EXPERIMENTAL APPROACH: Cognitive function was evaluated in behavioural experiments on male rats with HF. Transcriptomics and network pharmacology were used to identify potential pathways. Western blots, quantitative real-time polymerase chain reaction (qRT-PCR), Elisa, and electron microscopy were used to validate changes in identified pathways, brain inflammatory cytokines, postsynaptic membrane glutamate receptors and levels of apoptosis. Molecular docking and molecular dynamics simulation confirmed the binding ability of AS-IV and selected core proteins. KEY RESULTS: AS-IV improved cardiac function and disordered cardiac muscle structure in rats with HF. The advanced glycation end-products-receptor of advanced glycation end-products (AGE-RAGE) signalling pathway was the core pathway. AS-IV reduced the expression levels of RAGE, extracellular regulated protein kinases 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB). AS-IV also attenuated the expression of proinflammatory factors, increased the levels of anti-inflammatory factors, and up-regulated postsynaptic membrane glutamate receptor expression. Molecular docking and molecular dynamics simulation showed that AS-IV had favourable binding energy with RAGE. CONCLUSION AND IMPLICATIONS: AS-IV enhances cognitive function of HF rats by inhibiting the RAGE-ERK1/2-NF-κB signalling pathway to reduce inflammation and apoptosis and thereby improve synaptic function. AS-IV emerges as a promising candidate for the prevention and treatment of HF-CI.