Fingolimod Modulates the Gene Expression of Proteins Engaged in Inflammation and Amyloid-Beta Metabolism and Improves Exploratory and Anxiety-Like Behavior in Obese Mice.

ABSTRACT

Obesity is considered a risk factor for type 2 diabetes mellitus, which has become one of the most important health problems, and is also linked with memory and executive function decline. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates cell death/survival and the inflammatory response via its specific receptors (S1PRs). Since the role of S1P and S1PRs in obesity is rather obscure, we examined the effect of fingolimod (an S1PR modulator) on the expression profile of genes encoding S1PRs, sphingosine kinase 1 (Sphk1), proteins engaged in amyloid-beta (Aß) generation (ADAM10, BACE1, PSEN2), GSK3ß, proapoptotic Bax, and proinflammatory cytokines in the cortex and hippocampus of obese/prediabetic mouse brains. In addition, we observed behavioral changes. Our results revealed significantly elevated mRNA levels of Bace1, Psen2, Gsk3b, Sphk1, Bax, and proinflammatory cytokines, which were accompanied by downregulation of S1pr1 and sirtuin 1 in obese mice. Moreover, locomotor activity, spatially guided exploratory behavior, and object recognition were impaired. Simultaneously, fingolimod reversed alterations in the expressions of the cytokines, Bace1, Psen2, and Gsk3b that occurred in the brain, elevated S1pr3 mRNA levels, restored normal cognition-related behavior patterns, and exerted anxiolytic effects. The improvement in episodic and recognition memory observed in this animal model of obesity may suggest a beneficial effect of fingolimod on central nervous system function.