SEP-363856 attenuates CUMS-induced depression-like behaviours and reverses hippocampal neuronal injuries

Objectives: This study employed a chronic unpredictable mild stress (CUMS) model to examine the antidepressant properties of SEP-363856. Methods: The sucrose preference test (SPT) was employed to evaluate anhedonia, the open field test (OFT) to measure locomotor activity and exploratory behaviour, the elevated plus-maze (EPM) to assess anxiety-like behaviour, and the tail suspension test (TST) and forced swimming test (FST) to determine despair behaviour. qRT-PCR was implemented to evaluate gene expression levels in the hippocampus. Western blot, and ELISA were implemented to evaluate hippocampal protein expression, and Nissl staining was implemented to identify hippocampal neuronal injury. Results: The 10 mg/kg dosage of SEP-363856 and fluoxetine significantly improved depressive-like behaviours as assessed by the SPT, OFT, EPM, TST, and FST. This was associated with improved hippocampal neuronal damage, enhanced mRNA expression of brain-derived neurotrophic factor, synaptophysin, and postsynaptic density 95. SEP-363856 increased the levels of insulin-like growth factor-1 (IGF-1), IGF-1 receptor β, phospho-phosphatidylinositide 3-kinase, and phospho-protein kinase B in the brain. Conclusions: The antidepressant-like effects of SEP-363856 are linked to increased hippocampal neurotrophic factors, decreased hippocampus neuronal lesions, and activation of the IGF-1Rβ/PI3K/AKT signalling pathway. The latter may serve as a novel drug target for the treatment of depression.