ABSTRACT Background Licorice ( Glycyrrhiza spp.), a traditional Chinese herb, contains glycyrrhetinic acid derivatives with neuroprotective properties but limited bioavailability. Purpose YCY‐20 is a novel derivative synthesized by structural modification of 18 β ‐glycyrrhetinic acid. The aim of this study is to explore its therapeutic effect and potential molecular mechanism on cerebral ischemia–reperfusion injury (CIRI). Methods Pharmacokinetic profiling was performed to compare plasma exposure and brain distribution of YCY‐20 and its parent compound 18 β ‐GA. Neuroprotection was assessed using middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen–glucose deprivation/reoxygenation (OGD/R)‐induced HT22 cells. Evaluations included infarct volume (TTC staining), apoptosis (TUNEL, flow cytometry), and protein dynamics (Western blot). Network pharmacology identified potential targets, and in vivo experiments are conducted to validate the relevant molecular pathways. Results YCY‐20 exhibited improved pharmacokinetic properties, with higher and more stable plasma concentrations and detectable brain levels after oral administration, compared with 18 β ‐GA. YCY‐20 administration significantly attenuated body weight loss, cerebral infarct volume, and neuronal apoptosis in MCAO/R rats. Mechanistically, YCY‐20 suppressed the MCAO/R‐induced upregulation of pro‐apoptotic proteins (Bax, caspase‐3, cleaved caspase‐3) while restoring anti‐apoptotic Bcl‐2 expression. In vitro OGD/R models corroborated these anti‐apoptotic effects. Network analysis identified AGE‐RAGE/MAPK signaling as the predominant pathway modulated by YCY‐20, with subsequent in vivo validation demonstrating its capacity to downregulate key mediators in this pathway. Conclusions YCY‐20 confers protection against CIRI, at least partially through apoptosis inhibition mediated by AGE‐RAGE/MAPK signaling pathway modulation. This study provides preclinical evidence for developing licorice‐derived agents in stroke management.
Luo et al. (Sun,) studied this question.