FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

“…Activating PP2A by fingolimod leads to dephosphorylation and activation of mRNA-destabilizing protein tristetraprolin and reduces the production of TNF-α, IL-6, and IL-8 in early brain injury ( Yin et al, 2018 ). Anti-inflammatory effects of fingolimod (0.5 mg/kg) after TBI or ischemic stroke also occurs via restoration of the neurovascular unit by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes ( Cheng et al, 2021 ) or preventing the tight junction protein redistribution ( Wang Z. et al, 2020 ). Attenuation of iron deposition is also an outcome of fingolimod use in intracerebral hemorrhage ( Yang et al, 2019 ).…”

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury

“…Although the mechanism of action remains to be determined, a relationship between PP2A inhibition and claudin-5 expression in brain endothelial cells has been described [ 55 ]. Furthermore, it has been described, although not directly, that the PP2A activator FTY720 improved the BBB disruption after TBI, preventing brain edema by up-regulating claudin-5 [ 56 ]. However, FTY720 does not activate the HIF pathway and probably other PP2A isoforms are also involved in BBB protection.…”

Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice

“…24 ASIC 1 A contributes to inflammasome activation and inflammatory cytokines increase ASIC 1 A activity, providing a possible link between brain injury, IL-1 and ASIC activation. [50][51][52] Further work to test this hypothesis in repetitive mild TBI models is currently ongoing in our laboratory.…”