Sphingosine 1-Phosphate Receptor Subtype 1 as a Therapeutic Target for Brain Trauma

Abstract

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.

Keywords: CCI; S1PR1; TBI.