Exendin-4 protects brain endothelial cell damage against hyperammonemic condition

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with elevated ammonia levels, which impair blood-brain barrier (BBB) integrity and trigger chronic neuroinflammation. This study aims to evaluate the therapeutic potential of exendin-4, a glucagon-like peptide-1 receptor agonist, in mitigating BBB disruption and inflammation induced by hyperammonemia. We conducted experiments using a HE mouse model and in vitro cell culture systems. Using a bile duct ligation mouse model of HE, hepatic impairment was confirmed through significantly elevated serum aspartate aminotransferase and alanine aminotransaminase levels. Additionally, molecular cerebral changes were observed, including reduced tight junction protein expression and increased markers of oxidative stress and apoptosis. In an in vitro hyperammonemia model, we found that high ammonia levels significantly increased cell permeability, decreased tight junction protein expression (such as claudin-5) in bEnd.3 endothelial cells, and elevated pro-inflammatory cytokine secretion in C8-D1a astrocytes. Exendin-4 treatment effectively reversed these alterations, preserving BBB integrity and suppressing pro-inflammatory cytokine release. RNA sequencing further revealed transcriptional alterations in bEnd.3 endothelial cells after exendin-4 treatment. These findings highlight the potential of exendin-4 to mitigate hyperammonemia-induced BBB dysfunction, supporting its therapeutic value in treating neuropathologies associated with HE.