Abstract
Licochalcone A (LCA), a natural flavonoid with potent anti-inflammatory properties, has shown promise as a neuroprotective agent. However, its ability to cross the blood–brain barrier (BBB) and exert central effects remains underexplored. In this study, we demonstrate for the first time that LCA enhances cognitive function in a lipopolysaccharide (LPS)-induced neuroinflammatory mouse model and effectively penetrates the BBB. Following intraperitoneal administration of LCA (20 mg/kg), behavioral assessments via novel object recognition and Y-maze tests revealed significant improvements in non-spatial and spatial short-term memory. To investigate whether LCA is able to cross the BBB, we first developed and validated a sensitive GC–MS/MS method (LOD, 0.14 µg/mL; LOQ, 0.42 µg/mL) capable of quantifying LCA in brain tissue. The method revealed LCA brain concentrations peaking at 4 h ( T max ), with sustained levels above 15 µg/mg up to 8 h post-injection. Notably, LPS-pretreated animals exhibited higher BBB permeability to LCA, suggesting inflammation-enhanced CNS penetration. This is the first report to confirm LCA’s brain permeability and provide pharmacokinetics in brain tissue. Our findings not only validate the central neuroprotective potential of LCA but also establish a reliable analytical method for the detection of LCA. Graphical Abstract Licochalcone A (LCA) enhanced the cognition in the LPS-neuroinflammatory mouse model. To further understand its neuroprotective effect, a rapid sensitive GC–MS/MS bioanalytical method has been established to confirm LCA’s passage through the blood–brain barrier and perform a pharmacokinetics profiling in mice’s brain samples.