Nan Fang Yi Ke Da Xue Xue Bao. 2026 Sept 20;46(9):2130-2148. doi: 10.12122/j.issn.1673-4254.2026.09.13.
ABSTRACT
OBJECTIVES: To investigate the mechanism of genistein for alleviating cerebral ischemia/reperfusion (I/R)-induced neuroinflammation in microglia and its protective effects on co-cultured neurons.
METHODS: Male SD rats were divided into control group, I/R group, and 3 genistein groups treated with 25, 50 or 100 mg/kg genistein before I/R modeling (n=10), and the expressions of microglial polarization markers CD86 and CD206, inflammatory cytokines, PI3K, AKT, and COX-2 were examined. In cultured BV-2 cells with oxygen-glucose deprivation/reperfusion (OGD/R), the effects of genistein, si‑PI3K, genistein combined with si‑PI3K, 740Y‑P (a PI3K agonist), or 740Y‑P with genistein on microglial polarization, inflammatory factors, and PI3K, AKT and COX-2 expressions were assessed. In a neuron‑microglia co‑culture system, the changes in neuronal apoptosis rate, cell viability, and apoptosis‑related proteins in response to genistein treatment were detected.
RESULTS: The rat models of I/R exhibited obvious M1 polarization of the microglia, as shown by upregulated CD86, IL‑6, IL‑8, IL‑1β, TNF‑α, PI3K, AKT, and COX‑2 expressions and downregulated IL‑4 and TGF‑β expressions. Genistein treatment effectively reversed M1 polarization of the microglia, downregulated pro‑inflammatory factors and the PI3K/AKT/COX‑2 pathway, and promoted M2 polarization of the microglia in the mouse models. The COX‑2 inhibitor celecoxib produced similar effects to genistein by decreasing the expressions of M1 markers, TNF‑α, PI3K, AKT, and COX‑2 and increasing M2 markers and TGF‑β expression. In cultured BV-2 cells, genistein significantly inhibited OGD/R‑induced M1 polarization and pro‑inflammatory responses, and such protective effects were mimicked by PI3K knockdown, whereas PI3K activation by 740Y‑P partially counteracted the effects of genistein. In the neuron‑microglia co‑culture system, genistein obviously reduced OGD/R‑induced neuronal apoptosis, enhanced cell viability, decreased cleaved caspase‑3 and Bax expressions, and increased Bcl‑2 and BDNF expressions.
CONCLUSIONS: Genistein alleviates cerebral I/R-induced neuroinflammatory injury in rats by promoting M2 polarization of the microglia via downregulating the PI3K/AKT/COX‑2 pathway.
PMID:42812059 | DOI:10.12122/j.issn.1673-4254.2026.09.13