Abstract
Recent studies indicate that metabolic disorders such as diabetes and obesity are a major risk factor of psychiatric diseases. This relationship opens the opportunity to develop new antidepressant drugs by repurposing antidiabetic drugs. Previous research has demonstrated that GLP-1 analogs are neuroprotective in several neurological disease models including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In addition, the GLP-1 analog liraglutide has been shown to promote neurogenesis, which is seen to play important roles in memory formation and cognitive and emotional processing. However, whether liraglutide is an effective antidepressant remains unknown. Therefore, we tested this hypothesis in the depression model of chronic administration of corticosterone (CORT) in mice and treated the animals daily with liraglutide (5 or 20 nmol/kg ip.) to assess its therapeutic potential as an antidepressant. Behavioral studies showed that liraglutide administration attenuated depressive- and anxiety- like behaviors in this depression mouse model, and attenuated the hyperactivity induced by the stress hormone. Additionally, liraglutide treatment protected synaptic plasticity and reversed the suppression of hippocampal long-term potentiation induced by CORT administration, demonstrating synaptic protective effects of liraglutide. We also found that liraglutide treatment increased the cell density of immature neurons in the subgranular dentate gyrus region of the hippocampus. In addition, liraglutide prevented the CORT induced impairments and simultaneously increased the level of phosphorylated GSK3β in the hippocampus, which may be instrumental in the anti-depressant activity of liraglutide treatment. Taken together, liraglutide has the potential to act as a therapeutic treatment of depression.