Chronic heart failure (CHF) is increasingly recognized as a systemic syndrome with central nervous system consequences, including cognitive impairment. Neuroinflammation and maladaptive synaptic remodeling are considered key contributors to CHF-associated cognitive decline, yet mechanistically grounded interventions that target this heart–brain axis remain limited.
In a study published in the Chinese Journal of Natural Medicines , researchers evaluated whether Xijiaqi Formula (XJQ), a traditional Chinese medicine used clinically for CHF, can mitigate post-CHF cognitive dysfunction and clarified the underlying molecular circuitry. The authors first characterized XJQ constituents using liquid chromatography-mass spectrometry (LC-MS), then integrated network pharmacology with in vivo and molecular validation to prioritize candidate signaling nodes. To model CHF with cognitive impairment, rats underwent left anterior descending (LAD) coronary artery ligation, followed by six weeks of XJQ treatment. Cardiac status was assessed by echocardiography and hemodynamic parameters, and neurobehavioral performance was evaluated using the Morris water maze (learning/memory) and open-field testing (locomotor/exploratory behavior). XJQ improved both cardiac function and cognitive outcomes in CHF rats, supporting a dual cardiocerebral benefit in this preclinical setting.
Mechanistic analyses converged on phosphodiesterase-4 (PDE4)-dependent cyclic AMP signaling. Network pharmacology identified core active components and suggested that XJQ’s cognitive effects involve coordinated regulation of synaptic processes, inflammatory pathways, and PDE4-regulated cAMP signaling. Consistent with this framework, XJQ attenuated microglial and astrocytic activation, reduced pro-inflammatory cytokine levels, and mitigated neuronal injury markers in CHF animals, changes aligned with suppression of neuroinflammatory amplification that can impair cognitive circuitry.
XJQ also enhanced molecular signatures of neuroplasticity. The study reports that XJQ downregulated PDE4 while increasing cAMP, protein kinase A (PKA), and cAMP response element-binding protein (CREB) signaling, accompanied by increased expression of plasticity-associated factors including BDNF, PSD95, and synapsin I, together with evidence of improved synaptic repair and dendritic growth. These findings support a pathway model in which PDE4 inhibition and restoration of cAMP-dependent transcriptional programs promote synaptic resilience in CHF-associated cognitive dysfunction.
To strengthen target engagement, the authors combined computational and binding assays. Molecular docking and bio-layer interferometry supported direct binding of multiple XJQ-derived constituents, including quercetin, kaempferol, isorhamnetin, and darutoside, to PDE4, providing a plausible molecular basis for modulation of the PDE4/cAMP/PKA/CREB cascade.
Chinese Journal of Natural Medicines
Experimental study
Animals
Xijiaqi Formula attenuates cognitive dysfunction by inhibiting neuroinflammation and promoting neuroplasticity in rats with chronic heart failure
17-Mar-2025