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Abstract
BackgroundFTY720, an immunomodulator derived from a fungal metabolite which reduces circulating lymphocyte counts by increasing the homing of lymphocytes to the lymph nodes has recently gained interest in stroke research. The aim of this study was to evaluate the protective efficacy of FTY720 in cerebral ischemia in two different application paradigms and to gather first data on the effect of FTY720 on the rate of spontaneous bacterial infections in experimental stroke.MethodsMiddle cerebral artery occlusion (MCAO) in C57BL/6 mice (strain J, groups of 10 animals) was performed with two different durations of ischemia (90 min and 3 h) and FTY720 was applied 2 h after vessel occlusion to study the impact of reperfusion on the protective potency of FTY720. Lesion size was determined by TTC staining. Mice treated with FTY720 or vehicle were sacrificed 48 h after 90 min MCAO to determine the bacterial burden in lung and blood.ResultsFTY720 1 mg/kg significantly reduced ischemic lesion size when administered 2 h after the onset of MCAO for 3 h (45.4 ± 22.7 mm3 vs. 84.7 ± 23.6 mm3 in control mice, p = 0.001) and also when administered after reperfusion, 2 h after the onset of MCAO for 90 min (31.1 ± 28.49 mm3 vs. 69.6 ± 27.2 mm3 in control mice, p = 0.013). Bacterial burden of lung homogenates 48 h after stroke did not increase in the group treated with the immunomodulator FTY720 while there was no spontaneous bacteremia 48 h after MCAO in treated and untreated animals.ConclusionsOur results corroborate the experimental evidence of the protective effect of FTY720 seen in different rodent stroke models. Interestingly, we found no increase in bacterial lung infections even though FTY720 strongly reduces the number of circulating leukocytes.
Highlights
FTY720, an immunomodulator derived from a fungal metabolite which reduces circulating lymphocyte counts by increasing the homing of lymphocytes to the lymph nodes has recently gained interest in stroke research
The protective effect on lesion size was still present at 72 h after middle cerebral artery occlusion (MCAO) [8] and FTY720-treated mice performed better than controls in a behavioural test performed 15 days after experimental stroke [7]
In pilot experiments of the two application paradigms for FTY720 tested in this study, we found a reduction in lesion size of approximately 50% with a standard deviation of 0.33 to 0.5 of the lesion size leading to an effect size (Cohen’s d) of 1.697 [13]
Summary
FTY720, an immunomodulator derived from a fungal metabolite which reduces circulating lymphocyte counts by increasing the homing of lymphocytes to the lymph nodes has recently gained interest in stroke research. The aim of this study was to evaluate the protective efficacy of FTY720 in cerebral ischemia in two different application paradigms and to gather first data on the effect of FTY720 on the rate of spontaneous bacterial infections in experimental stroke. FTY720-phosphate can activate four of the five G protein-coupled S1P receptors known so far [4] It leads to a downregulation of autoimmuneinflammatory responses by inducing the internalization of the S1P1 receptor of lymphocytes and inhibits the lymphocyte egress from the lymph node into the systemic circulation [4], while the functional responses of the lymphocytes remain relatively unaltered [5]. The protective effect on lesion size was still present at 72 h after MCAO [8] and FTY720-treated mice performed better than controls in a behavioural test performed 15 days after experimental stroke [7]
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