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+ and CD8+, reduce the lesioned area (measured by 
2,3,5-triphenyltetrazolium chloride staining), and to preserve tissue 
architecture, microtubule stability, and neural plasticity. Moreover, our 
findings provide pre-clinical evidence for the use of low-dose oral S1PR1 
antagonists as neuroprotective strategies for TBI and broaden our understanding 
of the underlying S1PR1-driven neuroinflammatory processes in the 
pathophysiology of TBI. Altogether, our results showed that blocking the S1PR1 
axis is an effective therapeutic strategy to mitigate neuropathological effects 
engaged in the CNS by TBI.