[Effect of ganoderic acid A on delaying D-galactose-induced brain aging by modulating MAPK/SIRT1/NF-κB signaling...

This study aims to investigate the effects of ganoderic acid A(GAA) on delaying brain aging and elucidate its underlying mechanisms. Targets of GAA and brain aging were identified through network pharmacology databases. Intersection targets were subjected to protein-protein interaction(PPI) network analysis, gene ontology(GO) functional enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. Brain aging was induced in C57BL/6J mice via D-galactose administration, and GAA(25 or 50 mg·kg~(-1)) was delivered by oral gavage. The Y-maze and Morris water maze tests were used to assess neurobehavioral performance. Biochemical assays were employed to measure catalase(CAT) and glutathione(GSH) levels in brain tissue, as well as superoxide dismutase(SOD), glutathione peroxidase(GPx), and malondialdehyde(MDA) levels in serum. Enzyme-linked immunosorbent assay(ELISA) was used to quantify tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) levels in brain tissue. Immunohistochemistry was performed to evaluate hippocampal expression of ionized calcium-binding adapter molecule 1(Iba1) and glial fibrillary acidic protein(GFAP), while Western blot was utilized to determine protein expression levels of sirtuin 1(SIRT1), p38 mitogen-activated protein kinase(p38 MAPK), phosphorylated-p38 MAPK(p-p38 MAPK), extracellular signal-regulated kinases(ERK), phosphorylated-ERK(p-ERK), c-Jun N-terminal kinase(JNK), phosphorylated-JNK(p-JNK), nuclear transcription factor-kappa B p65(NF-κB p65), and phosphorylated-NF-κB p65(p-NF-κB p65). Network pharmacology analysis revealed 232 intersection targets between GAA and brain aging. Enrichment analysis indicated that these targets were associated with processes such as cell differentiation, apoptosis, and inflammatory response, involving 10 key signaling pathways including the MAPK signaling pathway. In animal experiments, GAA treatment significantly improved spatial exploration, learning, and memory abilities compared to the model group. Furthermore, GAA increased the levels of oxidative stress-related index CAT, GSH, SOD, and GPx, and reduced the MDA level. It also attenuated overactivation of Iba1 and GFAP in the hippocampus of aging mice, decreased TNF-α, elevated the IL-10 level, suppressed phosphorylation of ERK, JNK, p38 MAPK, and NF-κB p65, and upregulated SIRT1 expression. Collectively, GAA exerts multi-target neuroprotective effects against brain aging by modulating the MAPK/SIRT1/NF-κB signaling pathway, thereby alleviating oxidative stress and neuroinflammation.