GW-117

GW117 functions as both an MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist. This study aimed to investigate the anxiolytic effects of GW117 through behavioral assessments, including the open field test and novelty-suppressed feeding test (NSFT) within a chronic unpredictable mild stress (CUMS) model. GW117 was administered via oral gavage for 21 days to evaluate its sustained anxiolytic effects, with behavioral tests including the NSFT, the Vogel-conflict test, and the O-maze test. To explore the underlying mechanisms, we performed Western blot analyses to assess the expression levels of BCL2-Associated X (Bax), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP). Additionally, BrdU labeling and immunofluorescence staining were used to examine changes in neuronal regeneration and astrocytogenesis. Our results demonstrated that GW117 produced significant anxiolytic effects across all behavioral assays, both in the CUMS model and during long-term administration. Mechanistic studies revealed that GW117 notably increased the expression of BDNF, GFAP, and Bcl-2, while reducing Bax and cleaved caspase-3 levels in the hippocampus of CUMS model rats. Furthermore, the populations of BrdU-positive and GFAP-positive cells were elevated. These findings suggest that GW117 exerts anxiolytic effects, potentially through enhancements in hippocampal function.

Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/β-catenin signaling pathway.