Abstract
OBJECTIVES: To investigate the mechanism of Radix codonopsis combined with Poria (CRP) for improving cognitive impairment induced by permanent unilateral common carotid artery ligation (UCCA) in rats. METHODS: UPLC-Q-TOF-MS/MS and network pharmacology analysis were used to analyze the components of CRP in the blood and brain of rats medicated with CRP. Rat models of UCCA were treated with CRP gavage for 1 month, and Morris water maze, HE staining, and NeuN staining were used to assess the therapeutic efficacy. Metabolomics analysis, ELISA, immunohistochemistry, and Western blotting were employed to explore and validate the therapeutic mechanism of CRP. RESULTS: A total of 125 chemical constituents were identified in the brain tissue (89 Radix codonopsis components and 36 Poria components) and 126 in blood samples (85 Radix codonopsis components and 41 Poria components) of medicated rats. Network pharmacology analysis revealed that the therapeutic mechanism of CRP on dementia involved primarily the PI3K/Akt signaling pathway, regulated by the brain-targeting constituents of CRP. In UCCA rats, CRP treatment significantly improved their performance in Morris water maze test, alleviated neuronal damage in the hippocampus and cortex, and increased expression level of NeuN. Metabolomics analysis revealed significant enrichment of the estrogen and GABAergic synapse signaling pathways in CRP-treated rats. CRP obviously reduced the brain levels of glutamate and GABA/glutamate in UCCA rats, and downregulated the proteins expressions of ERα, p-PI3K/PI3K and p-Akt/Akt. CONCLUSIONS: CRP improves learning and memory impairment in UCCA rats possibly by modulating the ERα/PI3K/Akt signaling pathway in the brain.