Cabergoline possesses a beneficial effect on blood-brain barrier (BBB) integrity against lipopolysaccharide (LPS)

Abstract

ABSTRACT Sepsis is a disease induced by severe systemic inflammation and contributes to multiple acute organic dysfunctions. It is reported that disrupted blood-brain barrier (BBB) integrity is involved in sepsis-associated encephalopathy (SAE), which can be alleviated by repairing the damaged tight junction structure. Cabergoline is a specific dopamine D2 receptor agonist developed to treat Parkinson’s disease and hyperprolactinemia and is reported to exert promising anti-inflammatory properties. The present study aimed to explore the beneficial effect of Cabergoline for the treatment of sepsis. In the animal experiments, mice were separated into 4 groups: sham, LPS (5 mg/kg), Cabergoline (0.1 mg/kg/day), and Cabergoline+LPS. We found that the increased neurological deficits, disrupted BBB integrity, elevated production of inflammatory factors, and declined expression level of zonula occludens-1 (ZO-1) were observed in lipopolysaccharide (LPS)-treated mice, all of which were significantly reversed by the administration of Cabergoline. In the in vitro model, human brain microvascular endothelial cells (HBMECs) were challenged with 1 µg/mL LPS in the presence or absence of Cabergoline (10, 20 μM) for 24 hours. The elevated cell permeability Papp value of fluorescein disodium across the HBMECs monolayer and declined trans-endothelial electrical resistance (TEER) in the LPS-treated HBMECs were significantly alleviated by Cabergoline, accompanied by the upregulation of ZO-1. In addition, wnt1 and β-catenin were found downregulated, which was reversed by Cabergoline. Importantly, the protective benefits of Cabergoline were all abolished by the overexpression of Dickkopf 3 (DKK3). Taken together, our data reveal that Cabergoline possessed a protective effect on BBB integrity against LPS.