Abstract

Despite the widespread use of selective serotonin reuptake inhibitors like sertraline, the intricate molecular mechanisms underlying major depression and the therapeutic efficacy of these treatments remain not fully elucidated. Building on our preliminary findings, this study investigates the antidepressant effects of fasudil, a Rho-associated protein kinase (ROCK) inhibitor typically utilized as a vasodilator and antispasmodic, and compares its effects with those of sertraline using a chronic restraint stress model in rats. Specifically, we examined the effects of chronic administration on dendritic spine density, key molecular survival pathways, and miRNA levels in the hippocampus. Adult male Sprague-Dawley rats were administered sertraline, fasudil (10 mg/kg/day), or saline over 14 days, with a subset experiencing daily restraint stress. Our findings demonstrate that both sertraline and fasudil effectively prevented stress-induced reductions in dendritic spine density and miR-138 levels in the rat hippocampus. Additionally, by employing a network pharmacology approach, we explored the converging molecular pathways influenced by both drugs, facilitating the identification of novel molecular targets and pathways implicated in the pathophysiology of depression and its treatment. Pharmacoinformatic analysis revealed common signaling cascades and critical proteins that may potentially underlie the observed pharmacological effects, contributing to a paradigm shift in understanding depression by integrating drug repurposing and network pharmacology, offering valuable insights into the underlying mechanisms of depression and the antidepressant effect from a new network-based paradigm rather than focusing solely on a single protein target. © 2025 American Chemical Society.