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Siponimod (BAF312) Treatment Reduces Brain Infiltration but Not Lesion Volume in Middle-Aged Mice in Experimental Stroke
- Source :
- Stroke. 50:1224-1231
- Publication Year :
- 2019
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2019.
-
Abstract
- 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.
- Subjects :
- Male
Sphingosine 1 Phosphate Receptor Modulators
Pathology
medicine.medical_specialty
T-Lymphocytes
Central nervous system
Ischemia
Brain Ischemia
Lesion
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Benzyl Compounds
medicine
Animals
Neuroinflammation
030304 developmental biology
Advanced and Specialized Nursing
0303 health sciences
business.industry
Multiple sclerosis
Age Factors
Brain
medicine.disease
Pathophysiology
Mice, Inbred C57BL
Stroke
Disease Models, Animal
Treatment Outcome
Lymphatic system
medicine.anatomical_structure
Siponimod
chemistry
Azetidines
Neurology (clinical)
medicine.symptom
Cardiology and Cardiovascular Medicine
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15244628 and 00392499
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Stroke
- Accession number :
- edsair.doi.dedup.....9a0feb52fe555a0419dc1c5e7ee5d255