Abstract

This study explores the consequences of microRNA-665 suppression on depression, shedding light on the mechanisms involved through the phosphoinositide 3-kinase/protein kinase B/c-Jun N-terminal kinase signaling pathways. The findings aim to identify new therapeutic targets and offer deeper insights for treating depression. To model depression, mice were subjected to a chronic unpredictable mild stress protocol and subsequently distributed randomly into four groups; control, depression model, microRNA-665 silencing, and microRNA-665 silencing combined with phosphoinositide 3-kinase/protein kinase B inhibitor. MicroRNA-665 expression was silenced using adenoviral vectors. Serum cortisol levels were measured using enzyme-linked immunosorbent assay. In the depression model, silencing microRNA-665 notably decreased immobility duration in both the forced swim test and the tail suspension test. Additionally, it led to a significant increase in the total movement distance observed in the open field test. Enzyme-linked immunosorbent assay results showed a decrease in serum cortisol levels in the microRNA-665 silencing group. Reverse transcription-quantitative polymerase chain reaction analysis indicated that silencing microRNA-665 regulated the expression levels of phosphoinositide 3-kinase, protein kinase B, and c-Jun N-terminal kinase genes towards normal levels. Silencing miR-665 expression significantly improved the behavioral performance of depressed mice and normalized the levels of associated proteins and genes through the phosphoinositide 3-kinase, protein kinase B, and c-Jun N-terminal kinase signaling pathways, as well as regulated physiological indicators associated with depression.