Siponimod (BAF-312) Attenuates Perihemorrhagic Edema And Improves Survival in Experimental Intracerebral Hemorrhage

Abstract

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.

Brain transforms natural killer cells that exacerbate brain edema after intracerebral hemorrhage

“…Considering the potent cytotoxic and proinflammatory capacity of NK cells, these results suggest that prevention of NK cell infiltration into the brain might be a viable approach to reduce brain inflammation and attenuate PHE formation after ICH. In light of these studies, a randomized, placebo-controlled, subject-and investigator-blinded trial of another S1PR modulator, siponimod, in ICH patients is ongoing (NCT03338998; Bobinger et al, 2019). Although the benefits of S1PR modulation in improving outcome following ICH awaits more clinical evidence, immune modulation targeting lymphocytes to prevent PHE formation and neurological deterioration deserves further investigation.…”

A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH

“…In our proceeded paper ( https://www.ncbi.nlm.nih.gov/pubmed/31558140 ), we demonstrated that a second-generation selective S1P-receptor modulator, Siponimod, dose-dependently attenuated the development of secondary brain injury in acute stage of ICH, resulting in improved neurological functions of ICH animals in a short-time study [ 13 ]. Furthermore, we demonstrated that in long term, Siponimod increased the survival rate of treated compared to nontreated animals.…”

“…Furthermore, we demonstrated that in long term, Siponimod increased the survival rate of treated compared to nontreated animals. However, the long-term effects of Siponimod have not been further evaluated yet [ 13 ].…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Since peripheral immune cells (especially lymphocytes) do not play a role in organotypic slice culture models, this experimental setup has shown convincingly that siponimod can have beneficial effects in the context of MS by directly modulating the brain cell function. Accordingly, the protective effect of siponimod is not only limited to EAE but has also been observed in other models such as intracerebral hemorrhage [125], where it limits the formation of perihemorrhagic edema, and in experimental stroke [126], where it limits peripheral immune cell recruitment, as well as in a mouse model of diffuse large B-cell lymphoma [127].…”