Fingolimod Improves Anxiety-like Behavior and Modulates Sphingosine-1-Phosphate Receptors Gene Expression in a...

Type 2 diabetes mellitus (T2DM) is a rapidly expanding worldwide health issue associated with impairments in memory and executive functions. The bioactive sphingolipid sphingosine-1-phosphate (S1P) regulates cell death/survival and the inflammatory response by acting on S1P receptors (S1PRs). Unfortunately, the role of S1PRs signaling in the T2DM brain remains elusive.

The effect of fingolimod (FTY720, S1PRs modulator) on the behavior and expression profile of genes encoding S1PRs, sphingosine kinases (SPHK1 and 2), glucose transporters, proteins engaged in insulin signaling, sirtuin 1 (SIRT1), and proinflammatory cytokines in the brain cortex and hippocampus of diabetic mice was examined.

We observed a significant reduction in S1pr1, Sirt1, and insulin-like growth factor-1 (Igf1) gene expression that was accompanied by elevation of Sphk2, S1pr3, Il6, and Tnf in T2DM mice. Moreover, animals showed anxiety-like behavior and memory deficits. Fingolimod administration recovered downregulated S1pr1, Sirt1, and Igf1 expression and upregulated Slc2a4 (GLUT-4) and Ide (insulin-degrading enzyme). Furthermore, FTY720 reduced the elevated expression of Il6 and Tnf. Fingolimod also exerted an anxiolytic effect in T2DM.

Results indicate an important role of S1PR modulation in T2DM. Moreover, fingolimod affected mRNA levels of proteins engaged in glucose metabolism/insulin signaling and improved the behavior of diabetic mice.