The Effect of FTY720 on Brain Lipids, Ceramide, and TNF-α in Acute Cerebral Ischemia in Rats

Modulation of sphingosine-1-phosphate receptors exerts various neuroprotective effects under conditions of cerebral ischemia. In this study, we investigated the relationship between the lipid composition of brain tissue, lipid signaling, and the content of the proinflammatory cytokine TNFα, as well as the expression of its receptor, TNFR1.

 Objective. In a rat model of acute cerebral ischemia, to evaluate the effects of FTY720 on the lipid composition of brain tissue, ceramide concentration, and the expression of key enzymes involved in its synthesis, as well as on the contents of TNF-α and its receptor TNFR1.

Materials and Methods. The study was conducted on 37 male white non-linear rats weighing 180–230 g. Acute cerebral ischemia was induced by a combined procedure involving irreversible ligation of the left common carotid artery and reversible ligation of the right common carotid artery. The animals were divided into three groups: sham-operated, rats with acute cerebral ischemia, and rats with ischemia following prior administration of FTY720 (fingolimod). On the third day of observation, neurological deficits in surviving animals were assessed using the Garcia scale. The sphingolipid and phospholipid composition of brain tissue was examined using thin-layer chromatography. Ceramide concentration, the expression of enzymes involved in its biosynthetic, TNFα, and TNFR1 concentrations were evaluated using immunofluorescent microscopy.

Results. Pretreatment with fingolimod was associated with better survival rates: 31% in the FTY720 group vs. 20% in the Ischemia group (p = 0.043). Functional impairments on the Garcia scale were significantly less severe in the FTY720 group than in the Ischemia group: 14 [13.5; 15] vs. 11 [10; 12.5] scores (Me [Q1; Q3]), p < 0.01). FTY720 group also demonstrated a decrease in ceramide concentration in the brain tissue compared to the Ischemia group (p = 0.0005), along with downregulated expression of aSMase (p = 0.0012), nSMase (p = 0.0003) enzymes involved in its synthesis, of SPT (p = 0.0002), and CerS (p = 0.0001), a decrease in pro-inflammatory cytokine TNFα (p = 0.0003) concentration and normalized expression of its receptor TNFR1.

Conclusion. Preservation of phospholipid composition and reduction in the excessive production of ceramide and pro-inflammatory cytokines in the brain tissue are associated with less severe neurological deficits and improved survival rates in rats during the acute phase of cerebral ischemia.

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