Neuroprotective effects of Yangming-Kaixin-Yizhi formula in Alzheimer's disease: dual regulation of PI3K/Akt and p38 MAPK signaling via network pharmacology and experimental approaches.

Abstract

As a neurodegenerative disease characterized by progressive cognitive decline, the pathogenesis of Alzheimer's disease (AD) is still poorly understood, and there is no effective cure currently available. Traditional Chinese medicine (TCM) prescription Yangming-Kaixin-Yizhi formula (YKY) has been clinically applied for the treatment of memory loss related disorders for more than 300 years with remarkable efficacy, but its pharmacological mechanism remains unclear. This study aimed to investigate the therapeutic effects of YKY on AD and its molecular mechanisms. We evaluated YKY's ameliorative effects on the AD phenotype in 3xTg-AD mice using the Morris water maze, histopathological staining, and immunofluorescence assays. The major chemical components of YKY were identified by UPLC-QTOF-MS/MS. Network pharmacology was employed to analyze the molecular mechanisms of YKY in treating AD, followed by validation of its regulatory effects on key pathways through immunofluorescence experiments and molecular docking. The results showed that YKY could significantly improve learning and memory ability, neuronal loss, β-amyloid deposition and glial cell activation in 3xTg-AD mice. 48 chemical components were identified from YKY, and network pharmacology analysis of them showed that YKY may improve AD by regulating apoptosis, PI3K/Akt and MAPK pathways. Immunofluorescence and molecular docking results also confirmed the regulatory effect of YKY on key targets of apoptosis, PI3K/Akt and p38 MAPK pathways. In conclusion, by integrating animal experiments and network pharmacology, the present study revealed the mechanism of YKY in inhibiting neuronal apoptosis by regulating PI3K/Akt and p38 MAPK pathways, which providing modern scientific evidence for the traditional clinical application of YKY.