20( <i>R</i> )‐ginsenoside Rg3 Inhibits Neuroinflammation Induced by Cerebral Ischemia/Reperfusion Injury by Regulating the Toll‐Like Receptor 4/Myeloid Differentiation Factor‐88/Nuclear Factor Kappa B Signaling Pathway

20(R)-ginsenoside Rg3 can reduce the effects of oxidative stress and cell death in cerebral ischemia‒reperfusion injury (CIRI). Neuroinflammation is crucial post-CIRI, but how 20(R)-Rg3 affects ischemia‒reperfusion-induced neuroinflammation is unclear. To study 20(R)-Rg3's effects on neuroinflammation and neuronal preservation in stroke models and explore toll-like receptor 4/myeloid differentiation factor-88/nuclear factor kappa B (TLR4/MyD88/NF-κB) pathway mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuron injury were treated with 20(R)-Rg3; survival, cytokine levels, and pathway protein expressions were assessed; efficacy with the TLR4 inhibitor was also evaluated. In MCAO/R rats, 20(R)-Rg3 administration reduced inflammatory damage to brain tissue. 20(R)-Rg3 dose-dependently improved neuronal survival and attenuated inflammatory processes in OGD/R neurons. The expression levels of TLR4, MyD88, and phosphorylated NF-κB p65 are upregulated in MCAO/R rat brain tissue and OGD/R-induced neurons, and these effects are reversed by 20(R)-Rg3 treatment. In addition, 20(R)-Rg3 enhanced the anti-inflammatory efficacy of the TLR4 inhibitor TAK-242 and reduced inflammation in OGD/R-exposed neurons. 20(R)-Rg3 attenuates neuroinflammation and protects neurons via inhibiting TLR4/MyD88/NF-κB pathway in vitro and in vivo, suggesting it is a potential therapeutic for ischemic stroke.