Pharmacological inhibition of P2RX4 receptor as a potential therapeutic strategy to prevent intracranial aneurysm formation

Abstract

Intracranial aneurysms (IA) affect 1-5 % of the population and are a major cause of subarachnoid hemorrhage. Thus, preventing IA development and progression is crucial for public health. IA has been considered a non-physiological, high shear stress-induced chronic inflammatory disease affecting the bifurcation site of the intracranial arteries. Therefore, factors that sense high shear stress and induce IAs by triggering inflammation could potentially act as therapeutic targets. P2RX4 is a member of the purinoreceptor family that converts the strength of shear stress into intracellular signals. To verify its therapeutic potential, we investigated the effects of P2RX4 and a selective antagonist on the formation of IAs. Results showed that P2RX4 deficiency significantly suppressed the formation of IAs. Consistently, the selective P2RX4 antagonist NC-2600, which potently inhibited Ca²⁺ influx in response to shear-stress loading in endothelial cells in vitro, significantly suppressed the formation of IAs. The results of the present study contribute to our understanding of the pathogenesis of IAs and may provide benefits to society through the future development of medical therapies targeting P2RX4.

Keywords: High shear stress; Inflammation; Intracranial aneurysm; Medical therapy; P2RX4.