XiJiaQi Formula Attenuates Cognitive Dysfunction by Inhibiting Neuroinflammation and Promoting Neuroplasticity in Rats with Chronic Heart Failure (Manuscript ID: CJNM-2024-0848.R2, Accepted)

Chronic heart failure (CHF) impairs cognitive function. XiJiaQi Formula (XJQ), a traditional Chinese medicine is used clinically to treat CHF, and has shown potential in improving cognition in CHF patients. However, its exact mechanism to treat post-CHF cognitive dysfunction remains unclear. This study systematically investigates the effects of XJQ on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified by liquid chromatography-mass spectrometry. CHF was induced in rats by ligating the left anterior descending coronary artery and treated with XJQ for six weeks. Cardiac function was assessed by echocardiography and hemodynamic, while cognitive function was determined by Morris water maze and open field tests. XJQ treatment improved cardiac and cognitive functions in CHF rats. Network pharmacology predicted 12 core active components of XJQ, and suggested that its effect on cognitive dysfunction involved regulating synapse and inflammation, and PDE4-dependent cAMP signaling. XJQ inhibited the activation of microglia and astrocytes, reduced proinflammatory cytokines, and alleviated neuronal destruction. Importantly, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, PKA, CREB, BDNF, PSD95, and Synapsin I levels. The molecular docking and Bio-Layer interferometry assay confirmed that quercetin, kaempferol, isorhamnetin, darutoside directly bind to PDE4. In summary, XJQ relieves neuroinflammation and enriches synaptic plasticity to ameliorate cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling. These findings provide inspiring insight into the heart-brain axis.