GLP-1R Agonist Exendin-4 Protects Against Hemorrhagic Transformation Induced by rtPA After Ischemic Stroke via the Wnt/β-Catenin Signaling Pathway

Tissue plasminogen activator (tPA) is recommended by the FDA to dissolve intravascular clots after acute ischemic stroke (AIS). However, it may contribute to hemorrhagic transformation (HT). The Wnt/beta-catenin signaling pathway plays an important role in regulating the blood-brain barrier (BBB) formation in the central nervous system. We explored whether glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) reduces the risk of HT after rtPA treatment via the Wnt/beta-catenin pathway by using a rat transient middle cerebral artery occlusion (MCAO) model in vivo and an oxygen-glucose deprivation plus reoxygenation (OGD/R) model in vitro. Our results showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, BBB disruption, and rtPA-induced HT in ischemic stroke. EX-4 suppressed the production of ROS and the activation of MMP-9 to protect the integrity of the BBB by activating the Wnt/beta-catenin signaling pathway. PRI-724, a selective inhibitor of beta-catenin, was able to reverse the therapeutic effect of EX-4 in vivo and in vitro. Therefore, our results indicate that the GLP-1R agonist may be a potential therapeutic agent to decrease the risk of rtPA-induced HT after ischemic stroke via the Wnt/beta-catenin signaling pathway.

Automated summary

This study found that the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) has a protective effect against hemorrhagic transformation (HT) after ischemic stroke. The study showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, blood-brain barrier (BBB) disruption, and HT induced by thrombolytic therapy with tissue plasminogen activator (tPA). The protective effect of EX-4 was mediated by activating the Wnt/beta-catenin signaling pathway and suppressing reactive oxygen species (ROS) production and matrix metalloproteinase-9 (MMP-9) activation.