Prednisolone induces sleep disorders via inhibition of melatonin secretion by the circadian rhythm in zebrafish

Prednisolone (PN) is a glucocorticoid (GC) analog that is clinically used to treat allergic inflammation and autoimmune diseases. However, the long-term use of GC-like drugs results in many side effects, among which sleep disorders caused by PN have attracted much attention. Many studies have showed that GCs indirectly cause sleep disorders by disrupting the circadian rhythm of the peripheral biological clock. However, the detailed mechanism of this effect in zebrafish remains unclear. In the present study, we aimed to study the pharmacology and toxicology of PN by analyzing the sleep phenotype and internal circadian oscillation of zebrafish. Exposure of zebrafish to PN resulted in decreased melatonin secretion and shortened sleep time. Additionally, analysis of the internal circadian rhythm of the zebrafish revealed that the expression of per and cry was significantly upregulated, resulting in a significant delay in the phase of the zebrafish behavioral rhythm. A dual-luciferase reporter assay further revealed that PN repressed per2 and cry1aa expression via the GC receptor (GR), which inhibited aanat2 expression. This caused a decrease in melatonin secretion and led to sleep disorders. The findings of this study highlight the mechanisms underlying the effects of GCs on sleep.