Abstract W P233: FTY720 Preserves Arteriolar Vasodilating Function after Subarachnoid Hemorrhage

Abstract

Background: Inflammation is increasingly recognized as a key mediator of brain injury in subarachnoid hemorrhage (SAH). In this study we investigated the protective effect of the immunomodulatory agent, FTY720, on SAH. Methods: We utilized the endovascular perforation rat model of SAH. The animals were divided into three groups: (1) sham surgical control; (2) vehicle-treated SAH; and (3) FTY720-treated SAH. In group (2) and (3) rats received either vehicle solution or FTY720 (0.5 mg/kg) intraperitoneally 3h post-SAH. A close cranial window system was established at 48h post-SAH and intravital microscopy was used to assess (1) inflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in the pial venules, and (2) pial arteriolar dilating function to a variety of vasodilators including hypercapnia, acetylcholine (Ach), adenosine (ADA), and S-nitroso-N-acetyl penicillamine (SNAP). In addition, neurological function was evaluated at 48h using motor-sensory tests. Results: Compared to sham controls, the vehicle treated SAH animals had a 4-fold increase in pial venular leukocyte adhesion (2.90±0.6% vs. 14.4±2.7%; p<0.001). Treatment with FTY720 decreased leukocyte adhesion to 8.78±4.4% (p<0.05). Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and these were partially preserved in the presence of FTY720 (p<0.05; Table). In addition, neurological scores obtained at 48h post-SAH showed significant neurological deficits in the vehicle-treated group (10.8±2.1 vs. 20.5±0.4, vehicle vs. sham control) which was partially preserved by FTY720 (15.5±1.9; p<0.0001 compared to vehicle group). Conclusions: The use of FTY720 decreases the adhesion of leukocytes to pial vessels, preserves pial arteriolar FTY720 function, and improves the neurological outcome in rats subjected to SAH.