# Novel Glycyrrhizinic Acid Derivative YCY‐20 Inhibits Cerebral Ischemia/Reperfusion Induced Apoptosis via the AGE‐RAGE/MAPK Pathway

## TL;DR

A new licorice compound, YCY-20, protects brain cells from stroke damage by blocking a harmful signaling pathway.

## Contribution

YCY-20, a novel glycyrrhizinic acid derivative, shows improved bioavailability and neuroprotection via AGE-RAGE/MAPK pathway inhibition.

## Key findings

- YCY-20 has better pharmacokinetics and brain penetration than its parent compound.
- YCY-20 reduces cerebral infarct volume and neuronal apoptosis in stroke models.
- AGE-RAGE/MAPK pathway modulation is a key mechanism of YCY-20's neuroprotection.

## Abstract

Licorice (Glycyrrhiza spp.), a traditional Chinese herb, contains glycyrrhetinic acid derivatives with neuroprotective properties but limited bioavailability.

YCY‐20 is a novel derivative synthesized by structural modification of 18β‐glycyrrhetinic acid. The aim of this study is to explore its therapeutic effect and potential molecular mechanism on cerebral ischemia–reperfusion injury (CIRI).

Pharmacokinetic profiling was performed to compare plasma exposure and brain distribution of YCY‐20 and its parent compound 18β‐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.

YCY‐20 exhibited improved pharmacokinetic properties, with higher and more stable plasma concentrations and detectable brain levels after oral administration, compared with 18β‐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.

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.

Novel licorice‐derived compound YCY‐20 attenuates cerebral ischemia–reperfusion injury by suppressing neuronal apoptosis. Mechanistic studies reveal its neuroprotection is mediated through inhibition of the AGE‐RAGE/MAPK pathway, providing a preclinical foundation for stroke therapeutics development.