Siponimod (BAF-312) Attenuates Perihemorrhagic Edema And Improves Survival in Experimental Intracerebral Hemorrhage
| Autor: | Ralf A. Linker, Arnd Dörfler, Maximilian I. Sprügel, Stefan Schwab, Lisa Seyler, Tobias Bobinger, Tobias Bäuerle, Armin M. Nagel, Sebastian S. Roeder, Anatol Manaenko, Stephan von Hörsten, Petra Burkardt, Hagen B. Huttner, Vanessa D. Beuscher, Tobias Engelhorn |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Dose medicine.medical_treatment Brain Edema Pharmacology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Edema Benzyl Compounds medicine Animals Receptor Sphingosine-1-Phosphate Receptors Cerebral Hemorrhage 030304 developmental biology Advanced and Specialized Nursing Intracerebral hemorrhage 0303 health sciences medicine.diagnostic_test business.industry Multiple sclerosis Magnetic resonance imaging Immunosuppression medicine.disease Disease Models Animal Siponimod chemistry Azetidines Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Stroke. 50:3246-3254 |
| ISSN: | 1524-4628 0039-2499 |
| DOI: | 10.1161/strokeaha.119.027134 |
| Popis: | Background and Purpose— Perihemorrhagic edema (PHE) is associated with poor outcome after intracerebral hemorrhage (ICH). Infiltration of immune cells is considered a major contributor of PHE. Recent studies suggest that immunomodulation via S1PR (sphingosine-1-phosphate receptor) modulators improve outcome in ICH. Siponimod, a selective modulator of sphingosine 1-phosphate receptors type 1 and type 5, demonstrated an excellent safety profile in a large study of patients with multiple sclerosis. Here, we investigated the impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH. Methods— ICH was induced by intracranial injection of 0.075 U of bacterial collagenase in 123 mice. Mice were randomly assigned to different treatment groups: vehicle, siponimod given as a single dosage 30 minutes after the operation or given 3× for 3 consecutive days starting 30 minutes after operation. The primary outcome of our study was evolution of PHE measured by magnetic resonance-imaging on T2-maps 72 hours after ICH, secondary outcomes included evolution of PHE 24 hours after ICH, survival and neurological deficits, as well as effects on circulating blood cells and body weight. Results— Siponimod significantly reduced PHE measured by magnetic resonance imaging ( P =0.021) as well as wet-dry method ( P =0.04) 72 hours after ICH. Evaluation of PHE 24 hours after ICH showed a tendency toward attenuated brain edema in the low-dosage group ( P =0.08). Multiple treatments with siponimod significantly improved neurological deficits measured by Garcia Score ( P =0.03). Survival at day 10 was improved in mice treated with multiple dosages of siponimod ( P =0.037). Mice treated with siponimod showed a reduced weight loss after ICH ( P =0.036). Conclusions— Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in our experimental ICH-model. Findings encourage further investigation of inflammatory modulators as well as the translation of BAF-312 to a human study of ICH patients. |
| Databáze: | OpenAIRE |
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