Program

PO4-3-30

An S1P1 agonist, ASP4058, as a potential therapeutic candidate for intracranial aneurysm treatment

[Speaker] Rie Yamamoto:1,2
[Co-author] Tomohiro Aoki:1,3, Yoshitaka Hirayama:1,2, Ichiro Aramori:1,2, Shuh Narumiya:1
1:Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Japan, 2:Drug Discovery Research, Astellas Pharma Inc., Japan, 3:Department of Molecular Pharmacology, Research Institute, National Cerebral and Cardiovascular Center, Japan

Background:
Rupture of an intracranial aneurysm (IA) is the major cause of a life-threatening subarachnoid hemorrhage. Considering that IA is a relatively common disease (1~5%) in general population, prevention of IA progression and rupture is socially important. However, there is no medical therapy available for un-ruptured IAs. Recent studies suggest the involvement of chronic inflammation in intracranial arteries, caused by endothelial dysfunction and infiltrated macrophages, in the pathogenesis of IA. The aim of this study was thus to explore the potential of sphingosine-1-phosphate receptor type 1 (S1P1), expressed on the endothelium to maintain endothelial barrier, as a therapeutic target for IAs.

Methods:
A selective S1P1 agonist, ASP4058, was used. Its effects on endothelial permeability and trans-endothelial migration of monocytes were tested in vitro using a Transwell system. IAs were experimentally induced in Sprague-Dawley rats and ASP4058 was administered orally. Vascular permeability in the IA lesion was evaluated by a leakage of Evans blue intra-arterially injected. Effect of ASP4058 on size of induced IAs and macrophage infiltration in IA walls was evaluated by histological analysis.

Results:
S1P1 receptor was expressed in endothelial cells of both human and rat IA lesions. ASP4058 significantly reduced a leakage of FITC-labelled dextran across endothelial monolayer and also suppressed trans-endothelial migration of monocytic cells in vitro. Such an effect of ASP4058 was ameliorated by an addition of a selective S1P1 antagonist, thus confirming that ASP4058 exerts an inhibitory effect by acting on S1P1. In rat IA model, oral administration of ASP4058 significantly suppressed vascular permeability, macrophage infiltration and size of induced IAs. Importantly, two other structurally-unrelated S1P1 selective agonists both showed similar inhibitory effect on IA growth. Intriguingly, a non-selective S1P receptor agonist, fingolimod, failed to suppress but rather exacerbated IA progression, suggesting the importance of receptor subtype selectivity.

Conclusions:
We showed that selective S1P1 agonists suppress IA progression through maintaining the integrity of endothelial barrier and thus inhibiting trans-endothelial migration of macrophages. These findings indicate that S1P1 agonist can be a strong candidate of therapeutic agents for IA treatment.

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