Abstract
Ischemic stroke (IS) is a leading cause of death and long-term disability worldwide; however, effective neuroprotective therapies remain limited. Glabridin, a flavonoid from licorice, exhibits antioxidant and anti-inflammatory properties, making it a candidate for stroke therapy. To evaluate the therapeutic potential and mechanisms of glabridin in IS, we combined computational and experimental approaches. Network pharmacology and molecular docking were used to predict potential targets and pathways of glabridin in ischemic stroke. Functional validation employed a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse model (behavioral testing, TTC, HE, TUNEL/Nissl staining, and biochemical assays) and an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model in HT22 neuronal cells (cell viability assays and Western blot analysis). We found that glabridin significantly reduced infarct volume and improved neurological and motor function in MCAO/R mice, decreased neuronal apoptosis, attenuated inflammatory and oxidative stress markers (TNF-α, MDA) and increased antioxidant activity (SOD). In HT22 cells glabridin reduced OGD/R-induced apoptosis and restored cell viability. Mechanistically, both molecular docking and biochemical assays indicated that glabridin activates the PI3K/Akt signaling pathway, which likely mediates its neuroprotective effects. In summary, our integrative study demonstrates that glabridin ameliorates ischemia/reperfusion injury through anti-apoptotic, anti-inflammatory and antioxidant actions associated with PI3K/Akt activation, supporting further preclinical development.