Exendin-4 protects brain endothelial cells, restores BBB integrity in hyperammonemic HE mouse model

Patients with Hepatic Encephalopathy (HE) suffer from a severe neuropsychiatric disorder primarily driven by elevated ammonia levels. This hyperammonemia critically impairs the integrity of the blood-brain barrier (BBB) and triggers chronic neuroinflammation, leading to cognitive and motor dysfunction. Current therapeutic strategies largely focus on reducing ammonia production or absorption, but often fall short in directly addressing the BBB disruption and neuroinflammation that contribute significantly to HE pathology. Exploring agents like exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, offers a promising avenue due to its known neuroprotective and anti-inflammatory properties, potentially filling this therapeutic gap.

Researchers evaluated exendin-4's therapeutic potential in mitigating BBB disruption and inflammation in a HE mouse model and in vitro cell culture systems. The in vivo model utilized bile duct ligation (BDL) mice to induce hepatic impairment, confirmed by elevated serum aspartate aminotransferase and alanine aminotransaminase levels. In vitro, a hyperammonemia model was established using bEnd.3 endothelial cells and C8-D1a astrocytes. Cells were exposed to high ammonia levels, and then treated with Exendin-4. Primary endpoints included assessment of tight junction protein expression (claudin-5), cell permeability, markers of oxidative stress and apoptosis, and pro-inflammatory cytokine secretion. RNA sequencing was also performed on bEnd.3 cells to identify transcriptional changes. No specific dose or animal count (n) was detailed in the abstract.

In the HE mouse model, significant molecular cerebral changes were observed, including reduced tight junction protein expression and increased markers of oxidative stress and apoptosis, indicating BBB compromise. In the in vitro hyperammonemia model, high ammonia levels significantly increased cell permeability and decreased tight junction protein expression (specifically claudin-5) in bEnd.3 endothelial cells. Furthermore, ammonia exposure elevated pro-inflammatory cytokine secretion in C8-D1a astrocytes, confirming an inflammatory response. Exendin-4 treatment consistently reversed these detrimental effects.

Exendin-4 treatment effectively reversed these alterations, preserving BBB integrity and suppressing pro-inflammatory cytokine release.

This protective effect extended to mitigating oxidative stress and apoptosis markers. RNA sequencing analysis of bEnd.3 endothelial cells further revealed transcriptional alterations induced by exendin-4 treatment, suggesting a broad impact on cellular pathways involved in BBB function and inflammation. These findings collectively highlight exendin-4's capacity to counteract hyperammonemia-induced BBB dysfunction and neuroinflammation.