Abstract
BackgroundSubarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH.MethodsWe utilized an endovascular rat perforation model of SAH. Animals were divided into four groups: (1) sham-vehicle; (2) sham-fingolimod; (3) SAH-vehicle; and (4) SAH-fingolimod. Rats received either vehicle solution or fingolimod (0.5 mg/kg) intraperitoneally 3 hours after sham surgery or SAH. A closed cranial window and intravital microscope system was used at 48 hours to assess neuroinflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in pial venules, and pial arteriolar dilating responses to a variety of vasodilators, including hypercapnia, and topically-applied acetylcholine, adenosine, and S-nitroso-N-acetyl penicillamine. In addition, motor-sensory function was evaluated.ResultsCompared to sham-vehicle rats, SAH-vehicle animals displayed a four-times greater increase in pial venular intraluminal leukocyte adhesion. Treatment with fingolimod largely reduced the intravascular leukocyte adhesion. Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and vascular reactivity was preserved, to a significant degree, in the presence of fingolimod. In addition, neurological scores obtained at 48 hours post-SAH indicated significant neurological deficits in the vehicle-treated group (versus sham-vehicle surgical control). Those deficiencies were partially reduced by fingolimod (P < 0.0001 compared to the vehicle-treated SAH group).ConclusionsTreatment of rats with fingolimod was associated with a marked limitation in the intravascular adhesion of leukocytes to pial venules, preserved pial arteriolar dilating function, and improved neurological outcome in rats subjected to SAH.
Highlights
Subarachnoid hemorrhage (SAH) is associated with a disproportionately elevated morbidity and mortality
Studies performed in association with cerebral ischemia and intraparenchymal hemorrhage have shown that FTY720 reduces stroke-related neuroinflammation, brain edema, and neuronal death and improves neurological outcome [15,16,17]
Similar surgical procedure was performed in sham-vehicle and FTY720 groups except that the suture was removed once resistance was felt and no tungsten wire perforation was performed
Summary
Subarachnoid hemorrhage (SAH) is associated with a disproportionately elevated morbidity and mortality. Xu et al Journal of Neuroinflammation (2015) 12:16 role in brain damage by contributing to neural injury, diminished vascular reactivity, microthrombosis, and enhanced blood brain barrier (BBB) permeability [7,8,11,12]. These observations support immunomodulation as a potential target for intervention following SAH. Studies performed in association with cerebral ischemia and intraparenchymal hemorrhage have shown that FTY720 reduces stroke-related neuroinflammation, brain edema, and neuronal death and improves neurological outcome [15,16,17]. We examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH
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