Background: Ischemic stroke is associated with impaired endothelial eNOS/NO signaling. Gintonin, an LPAR ligand from Korean ginseng, has neuroprotective properties. We investigated whether gintonin protects against ischemic stroke by restoring eNOS/NO signaling.

Methods:Human brain microvascular endothelial cells were subjected to oxygen–glucose deprivation (OGD) with gintonin treatment. NO production, eNOS expression, and cell viability were assessed, and LPAR dependence was evaluated using Ki16425. The protective effects of oral gintonin were further examined in a NOS inhibitor-mediated ischemic stroke model (NAIM) in C57BL/6 mice.

Results:Gintonin restored NO production, increased eNOS mRNA expression, and improved cell viability under OGD conditions. These effects were blocked by Ki16425, indicating LPAR-dependent protection. In NAIM mice, gintonin pretreatment significantly improved 7-day survival (65.0% vs. 48.3%, p=0.009) and reduced infarct severity (p=0.02), although infarct volume among survivors was unchanged.

Conclusion:Gintonin protects against ischemic stroke by enhancing endothelial eNOS/NO signaling through LPAR activation and may have potential as a preventive strategy for acute ischemic stroke.