Background and Purpose- The contribution of neuroinflammation and, in 
particular, the infiltration of the brain by lymphocytes is increasingly 
recognized as a substantial pathophysiological mechanism after stroke. The 
interaction of lymphocytes with endothelial cells and platelets, termed 
thromboinflammation, fosters microvascular dysfunction and secondary infarct 
growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which 
blocks the egress of lymphocytes from lymphoid organs and has demonstrated 
beneficial effects in multiple sclerosis treatment. We investigated the effect 
of treatment with siponimod on stroke outcome in a mouse model of cerebral 
ischemia. Methods- Transient middle cerebral artery occlusion was induced in 
middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; 
intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic 
resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: 
days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune 
cells of the peripheral blood and brain-infiltrating cells ipsilateral and 
contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod 
significantly induced lymphopenia on day 7 after transient middle cerebral 
artery occlusion and reduced T-lymphocyte accumulation in the central nervous 
system. No effect was detected for lesion size. Conclusions- For siponimod 
administered at 3 mg/kg in transient middle cerebral artery occlusion mouse 
model, our findings do not provide preclinical evidence for the use of S1PR1/5 
modulators as neuroprotectant in stroke therapy.