Esculentoside H reduces the PANoptosis and protects the blood-brain barrier after cerebral ischemia/reperfusion through the TLE1/PI3K/AKT signaling pathway

Aims: Matrix Metalloproteinases 9 (MMP9) plays a role in the destruction of blood-brain barrier (BBB) and cell death after cerebral ischemic/reperfusion (I/R). Esculentoside H (EH) is a saponin found in Phytolacca esculenta. It can block JNK1/2 and NF-κB signal mediated expression of MMP9. In this study, we determined whether EH can protect against cerebral I/R injury by inhibiting MMP9 and elucidated the underlying mechanism.

Main methods: Male SD rats were used to construct middle cerebral artery occlusion (MCAO) models. We determined the effect of EH on MMP9 inhibition, BBB destruction, neuronal death, PANoptosis, infarct volume, and the protective factor TLE1. Adeno-associated virus (AAV) Infection was used to establish TLE1 gene overexpression and knockdown rats, which were used to determine the function. LY294002 was used to determine the role of PI3K/Akt signaling in TLE1 function.

Key findings: After EH treatment, MMP9 expression, BBB destruction, neuronal death, and infarct volume decreased. We found that TLE1 expression decreased obviously after cerebral I/R. TLE1-overexpressing rats revealed distinct protective effects to cerebral I/R injury. After treatment with LY294002, the protective effect was inhibited. The curative effect of EH also decreased when TLE1 was knocked down.

Significance: EH alleviates PANoptosis and protects BBB after cerebral I/R via the TLE1/PI3K/Akt signaling pathway. Our findings reveal a novel strategy and new target for treating cerebral I/R injury.

Blood–brain barrier; Cerebral ischemia; Esculentoside H; PANoptosis; PI3K/AKT; TLE1.