Intervention effect of regulating GABA-A receptor activity on the formation of experimental abdominal aortic aneurysm in rats

Abstract

Abdominal aortic aneurysm is a potentially fatal vascular inflammatory disease characterized by infiltration of various inflammatory cells.The GABA-A receptor is expressed in many inflammatory cells such as macrophages and T cells and has anti-inflammatory and antioxidant effects. Therefore, the GABA-A receptor may become a potential therapeutic target for abdominal aortic aneurysms. The purpose of this study was to investigate the effect of regulating the activity of the GABA-A receptor on the formation of experimental abdominal aortic aneurysm in rats. In this study, the abdominal aortic aneurysm model of rats was established by aorta intracavitary perfusion of elastase combined with aorta extracavitary infiltration of calcium chloride. GABA-A receptor agonist (topiramate) and antagonist (bicuculline) were used to treating the abdominal aortic aneurysm model rats, which were divided into sham operation group, model group, topiramate group, and bicuculline group( n = 10). Histopathology, immunohistochemistry, fluorescence quantitative PCR, Western blotting, ELISA and Gelatine zymogram were used to study. Regulation of GABA-A receptor activity can interfere with the development and severity of abdominal aortic aneurysms in rats. The GABA-A receptor agonist topiramate reduces the infiltration of inflammatory cells, particularly T cells, into the abdominal aortic wall, while also modulating the balance of Th1/Th2 cytokines in peripheral blood, leading to a significant reduction in inflammatory responses. Additionally, topiramate decreases the secretion of matrix metalloproteinases MMP2 and MMP9, thereby inhibiting extracellular matrix degradation and slowing the progression of aneurysms. In contrast, the GABA-A receptor antagonist bicuculline exacerbates inflammation and promotes aneurysm development. At the molecular level, the mechanisms of action of the GABA-A receptor agonist topiramate and the antagonist bicuculline may involve inhibition or activation of the p38 MAPK signaling pathway. Regulation of GABA-A receptor activity can effectively intervene in the occurrence and development of abdominal aortic aneurysms in rats.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-82913-7.