Antidepressant Effect of Intermittent Long‐Term Systemic Administration of Irisin in Mice

Depression is a psychiatric disorder increasingly diffused worldwide. Evidence suggests that irisin, a myokine secreted by contracting muscle, mediates beneficial effects on several targets, including the brain. Here, the potential antidepressant properties of long‐term intermittent systemic irisin administration (100 μg/kg/weekly for 1 month) were evaluated in mice by the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Furthermore, to deepen the molecular pathways underlying irisin treatment, the expression of irisin precursor, neurotrophic/growth factors, and cytokines was analyzed. Irisin treatment significantly decreased the immobility time in the TST and FST, suggesting an antidepressant effect. Additionally, irisin seemed to display an an-xiolytic‐like effect increasing the time spent in the OFT arena center. These findings were probably due to the modulation of endogenous brain factors as the gene expression of some neurotrophins, such as brain‐derived neurotrophic factor (BDNF) and insulin‐like growth factor (IGF‐1), was up-regulated only in irisin‐treated mouse brain. Moreover, irisin modulated the expression of some cytokines (IL‐1β, IL‐4, IL‐6, and IL‐10). To the best of our knowledge, this is the first study demon-strating that the irisin antidepressant effect may be observed even with a systemic administration in mice. This could pave the way toward intriguing preclinical research in humans.