Adiponectin peptide alleviates oxidative stress and NLRP3 inflammasome activation after cerebral ischemia-reperfusion injury by regulating AMPK/GSK-3β.

The effects of current treatment strategies for ischemic stroke are weakened by ischemia-reperfusion (I/R) injury. Effective treatments targeting I/R injury are still insufficient. Adiponectin (APN), a fat-derived hormone, has a wide range of antioxidative and anti-inflammatory effects. However, the application of APN to the central nervous system is restricted by its limited blood-brain barrier permeability. Therefore, an adiponectin peptide (APNp) was chemically synthesized on the basis of the functional area in the APN structure. The present study was carried out to explore the effect and the underlying mechanism of APNp on I/R injury. A transient middle cerebral artery occlusion (tMCAO) model with C57BL/6 J mice was used, and an in vitro oxygen-glucose deprivation and reintroduction (OGD-R) model with primary astrocytes was induced. The results showed that APNp decreased the cerebral infarction volume, alleviated brain edema, improved neurological function and had antioxidative, anti-inflammatory, and antiapoptotic effects against cerebral I/R injury. In addition, APNp upregulated the phosphorylation of AMPK and GSK-3β, promoted the nuclear translocation of Nrf2 and increased the expression of Trx1. The protective effect of APNp was abolished by compound C, a selective AMPK inhibitor, and PX-12, a selective Trx inhibitor. Moreover, APNp decreased the protein level of TXNIP and suppressed the activation of the NLRP3 inflammasome in astrocytes, which were also reversed by compound C and PX-12. These findings suggest that APNp, as a potential substitute for adiponectin, has a great potential for clinical application in the treatment of acute brain ischemia.