Abstract WP76: Shear Stress Sensing on the Endothelium Initiates Chronic Inflammation of the Arterial Wall During Cerebral Aneurysm Formation Potential Novel Therapy for Cerebral Aneurysms With Paroxetine

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Background and purpose: It is thought that the cerebral aneurysm is caused by chronic inflammation of the arterial wall. However, it is still not clear what triggers the inflammation. We hypothesize that shear stress-related hemodynamics initiates cerebral aneurysm formation, and have reported that disruption of the endothelial shear stress sensor, P2X4 purinoceptor, significantly reduces cerebral aneurysm formation using knockout mice of the sensor. We examined here whether inhibition of P2X4 purinoceptor has any influence on expressions of inflammatory contributors to aneurysm formation or not.Methods: Sprague-Dawley rats (n = 61) were subjected to cerebral aneurysm-generating surgery with ligation of unilateral common carotid artery and renal hypertension, and the P2X4 purinoceptor inhibitor, paroxetine (8 mg/kg/day) was administered after the surgery for 3 weeks. The incidence of aneurysm formation was examined with light microscopy and expressions of inflammatory contributors to aneurysm formation using a quantitative real-time PCR analysis.Results: Paroxetine significantly attenuated the incidence of induced aneurysms in rats after aneurysm-generating surgery (p = 0.031, Wilcoxon/Kruskal-Wallis test). Expression levels of known inflammatory contributors to aneurysm formation, COX-2, TNFα, MCP-1, IL1β, and iNOS, were significantly increased in rats after aneurysm-inducing surgery than control non-operated animals by a quantitative real-time PCR analysis. Paroxetine significantly reduced the expression levels of COX-2, TNFα, MCP-1, IL1β, and iNOS (p = 0.0019, 0.0101, 0.0019, 0.0239, 0.0101, respectively).Conclusions: These data suggest that shear sensing on the arterial endothelium initiates chronic inflammation in the arterial wall during cerebral aneurysm formation. Because 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.

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