Fingolimod reduces blood-brain barrier damage, inflammation, and neuronal death in experimental subarachnoid hemorrhage.

Abstract

Subarachnoid hemorrhage (SAH) is a severe form of hemorrhagic stroke associated with high morbidity and mortality. There are limited pharmacological treatment options available to prevent or treat secondary neurologic injury after SAH. We have previously shown that the immunomodulatory agent fingolimod (FTY720) reduces early adhesion of leukocytes to pial venules, preserves pial arteriolar dilating function, and improves neurologic outcome in a rodent model of SAH. However, the direct effect on cells residing within the brain is less well understood. We employed the endovascular perforation model of SAH in 6-8-week-old male rats to measure blood-brain barrier damage, downstream pro-inflammatory signaling pathways in microglia and astrocytes, and neuronal cell death. Animals were divided into sham, SAH-vehicle, and SAH-FTY720 groups. The SAH-FTY720 group received a single dose of fingolimod (0.5 mg/kg) intraperitoneally, three hours after surgery to replicate timing in which acute interventions can be administered following SAH. Blood-brain barrier dysfunction was seen in SAH-vehicle animals based on Evans blue extravasation and cerebral water content. Microglia and astrocytes increase expression of nitric oxide synthase after SAH, and microglia in particular upregulate NF-ĸB signaling. These changes are associated with neuronal cell death. Treatment with FTY720 improves blood-brain barrier integrity, inhibits pro-inflammatory signaling within microglia and astrocytes, and decreased neuronal apoptosis in the rat cortex and hippocampus. This data further elucidates proinflammatory and neurotoxic pathways activated within the brain following SAH, and suggests that immunomodulation with FTY720 has a beneficial effect on several pathogenic mechanisms of SAH-associated brain injury.