siponimod and Brain-Injuries--Traumatic

Traumatic brain injury (TBI) provokes secondary pathological mechanisms, including ischemic and inflammatory processes. The new research in sphingosine 1-phosphate (S1P) receptor modulators has opened the door for an effective mechanism of reducing central nervous system (CNS) inflammatory lesion activity. Thus, the aim of this study was to characterize the immunomodulatory effect of the functional S1PR1 antagonist, siponimod, in phase III clinical trials for autoimmune disorders and of the competitive sphingosine 1-phosphate receptor subtype 1 (S1PR1) antagonist, TASP0277308, in pre-clinical development in an in vivo model of TBI in mice. We used the well-characterized model of TBI caused by controlled cortical impact. Mice were injected intraperitoneally with siponimod or TASP0277308 (1 mg/kg) at 1 and 4 h post-trauma. Our results demonstrated that these agents exerted significant beneficial effects on TBI pre-clinical scores in term of anti-inflammatory and immunomodulatory effects, in particular, attenuation of astrocytes and microglia activation, cytokines release, and rescue of the reduction of adhesion molecules (i.e., occludin and zonula occludens-1). Moreover, these compounds were able to decrease T-cell activation visible by reduction of CD4

Topics: Animals; Azetidines; Benzyl Compounds; Brain Injuries, Traumatic; Male; Mice; Neuroprotective Agents; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Sulfones; Triazoles