Inhibition of P2X4 purinoceptor reduces growth of the cerebral aneurysm

Abstract

BackgroundRupture of a cerebral aneurysm is a major cause of life‐threatening subarachnoid hemorrhage. However, there are no effective therapeutic drugs for the treatment of aneurysms, partly because the pathogenesis of the aneurysm remains unresolved. Although chronic inflammation of the cerebral arterial wall plays an important role in aneurysm formation, it is not clear what triggers the inflammation. We previously reported that inhibition of the endothelial shear stress sensor, P2X4 purinoceptor, significantly reduces mRNA expressions of known inflammatory contributors to aneurysm formation, leading to suppression of aneurysm induction. We examined here whether inhibition of P2X4 has any influence on cerebral aneurysm ‘growth’ or not.MethodsSprague‐Dawley rats were subjected to cerebral aneurysm‐generating surgery with ligation of unilateral common carotid artery and renal hypertension. P2X4 purinoceptor inhibitor, paroxetine (8 mg/kg/day) was administered to rats. Three weeks after the surgery, the aneurysm size was examined with light microscopy, and protein expressions of contributors to aneurysm formation using Western blotting.ResultsThe cerebral aneurysm‐inducing surgery induced an aneurysm in 100% of rats 2 weeks after the surgery. Application of paroxetine from 2 weeks after surgery led to a significant reduction in aneurysm size in the rats sacrificed 3 weeks after aneurysm‐inducing surgery (p=0.0145), indicating that paroxetine suppressed enlargement of formed aneurysms. The protein expression levels of known inflammatory contributors to aneurysm formation (MCP‐1, IL1ß, TNFα, iNOS, and COX‐2) were all significantly elevated in the rats that underwent the aneurysm‐inducing surgery compared to the non‐surgical group, and the values in the surgical group were all significantly decreased by paroxetine administration.ConclusionThe data suggest that P2X4 is required for the cerebral aneurysm growth. Enhanced shear stress‐associated hemodynamic stress on the vascular endothelium may trigger the cerebral aneurysm enlargement. Since paroxetine has been used for human as an antidepressant, clinical use of this P2X4 purinoceptor inhibitor is expected as a novel therapy for cerebral aneurysms.Support or Funding InformationThis work was supported by the Japan Agency for Medical Research and Development (AMED) under grant no. JP15gm0810006h0301, a JSPS KAKENHI grant (no. 15K10323), and The Shimizu Foundation for Immunology and Neuroscience.