Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats.

Although there is evidence that sphingosine-1-phosphate receptor-1 (S1P1) activation occurs following experimental brain injury, there is little information about its metabolic pathway in cerebral ischemia. The purpose of this study was to evaluate the role of the sphingosine metabolic pathway including S1P1, sphingosine kinases 1 (SphK1), and 2 (SphK2) in transient middle cerebral artery occlusion (MCAO). Fifty-eight male Sprague-Dawley rats were used to asses temporal profiles of S1P1, SphK1 and 2 on neurons in infarct and periinfarct cortices at pre-infarct state, 6, and 24 hours after MCAO. The animals were then treated with vehicle and 0.25 mg/kg FTY720, which is an agonist of S1P receptors, and evaluated regarding neurological function, infarct volume, and S1P1 expression on neurons at 24 hours after MCAO. The expressions of S1P1, SphK1, and SphK2 were significantly decreased after MCAO. Labeling of all markers were reduced in the infarct cortex but remained present in the periinfarct cortex, and some were found to be on neurons. Significant improvements of neurological function and brain injury were observed in the FTY720 group compared with the vehicle and untreated groups, although S1P1 expression on neurons was reduced in the FTY720 group compared with the vehicle group. We demonstrated that S1P1, SphK1, and SphK2 were downregulated in the infarct cortex, whereas they were preserved in the periinfarct cortex where FTY720 reduced neuronal injury possibly via S1P1 activation. Our findings suggest that activation of the sphingosine metabolic pathway may be neuroprotective in cerebral ischemia.