A Study on the Mechanism of Action of Isorhamnetin in the Treatment of Depression using Network Pharmacology, Molecular Docking Technology and Experimental Validation.

OBJECTIVE: This study aimed to investigate the antidepressant mechanism of isorhamnetin based on the common targets and signaling pathways shared by depression and type 2 diabetes mellitus. METHOD: The targets and mechanisms of isorhamnetin's action on depression were investigated by network pharmacology and molecular docking experiments, combined with 100 ns molecular dynamics simulation to verify the binding stability, and the effects of the related mechanisms were verified at the animal level, including Western blot analysis of p-GSK-3β phosphorylation. RESULT: The results showed that isorhamnetin could act on 80 potential targets and participate in the regulation of 198 related signaling pathways in the treatment of depression. It exerted potential antidepressant effects by improving glucose metabolism disorders in mice and regulating the signaling pathways comorbid with depression and diabetes. DISCUSSION: An in-depth topological analysis demonstrated that isorhamnetin exhibited the highest degree of interaction. Direct inhibition of depression proteins by isorhamnetin and GSK-3β was validated using reverse docking validation. The effect of isorhamnetin on diabetic mice showed that isorhamnetin inhibits the activity of dipeptidyl peptidase-4 in a dose-dependent manner, promoting the secretion of glucagon-like peptide-1, and then inhibiting the activity of GSK- 3β, which contributes to the lowering of blood glucose while activating the PI3K/AKT signaling pathway, triggering a cascade reaction that subsequently regulates the expression profiles of depression- associated targets in the downstream signaling pathway. Data obtained via molecular docking experiments demonstrated that isorhamnetin binds to GSK-3β in the vicinity of its catalytic region, thereby blocking the binding of GSK-3β to its target substrate. CONCLUSION: This study elucidated the mechanism by which isorhamnetin exerts potential antidepressant effects by regulating the common targets and signaling pathways of depression and diabetes, and provided a theoretical basis for its clinical application.