Fingolimod protects against cerebral ischemia reperfusion injury in rats by reducing inflammatory cytokines and inhibiting the activation of p38 MAPK and NF-κB signaling pathways

Abstract

Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor agonist. Here, to understand biological activity of FTY720 pretreatment and post-treatment on cerebral ischemia reperfusion injury (CIRI), rat transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model was generated. Neurological deficit scoring was assessed after tMCAO/R. Four groups were established including sham-operated control group, operated group, and two FTY720-treated groups. Neuron damage was observed by Nissl staining. Gene expression was measured using qPCR and western blot analysis. Tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) levels were evaluated by enzyme-linked immunosorbent assay (ELISA). We uncovered that neurological score in two FTY720-treated groups was significantly lower than that in the operated group. FTY720 pretreatment or posttreatment groups had a significantly increased number of Nissl bodies in cerebral cortex as compared with the operated group, indicating that FTY720 administration reduced neuronal damage. Besides, FTY720 posttreatment improved memory impairment induced by tMCAO/R. In addition, IL-1β, IL-6, and TNF-α levels in the cerebral cortex and hippocampus of two FTY720-treated groups were significantly decreased in comparison to the operated group, showing that FTY720 could reduce the release of inflammatory cytokines in brain tissue. Furthermore, phosphorylation of p38MAPK and NF-κB pathway-related molecules in ischemic brain tissues of FTY720 group were markedly down-regulated compared to the operated group. Together, FTY720 pretreatment or posttreatment improved the neurological deficit of middle cerebral ischemia/reperfusion rat model and reduced neuronal damage by decreasing the levels of inflammatory cytokines and attenuating the phosphorylation levels of p38MAPK and NF-κB pathway-associated molecules. FTY720 exhibits neuroprotective effects against ischemic reperfusion injury in rats.