Amelioration of Gap Junction Dysfunction in a Depression Model by Loganin: Involvement of GSK-3β/β-Catenin Signaling

Ethnopharmacological relevance: Comus officinalis Sieb. et Zucc has significant neuroprotective activity and has been widely studied for its potential to improve cognitive function. Our team's previous research has found that loganin isolated from Comus officinalis has an antidepressant effect. Depression is a mental disorder accompanied by dysfunction of Connexin43 (Cx43)-formed astrocytic gap junctions. However, the precise mechanisms of loganin involved remain uncertain.

Aim of the study: We aimed to examine the mechanism by which loganin produces its antidepressant properties.

Materials and methods: Using a chronic unpredictable stress (CUS) model of depression in rats, the study evaluated the behavioral responses to treatment with loganin, fluoxetine, and their combination. Biochemical analyses were conducted to measure the expression and phosphorylation status of Cx43, β-catenin, GSK-3β in the brain. In vitro experiments were also performed how loganin protects the gap junctions in astrocytes that have been exposed to corticosterone.

Results: After four weeks of loganin treatment, rats exposed to CUS showed a decrease in depressive-like behaviors. When combined with fluoxetine, the antidepressant-like effects were observed faster than with either treatment alone. Loganin significantly increased Cx43 expression in the prefrontal cortex and ventral hippocampus, reversed Cx43 mimetic peptide Gap26-induced depressive-like behaviors, decreased Cx43 phosphorylation at Ser368, increased β-catenin levels, and promoted GSK-3β phosphorylation at Ser9. In vitro, loganin prevented corticosterone-induced damage to gap junctions between astrocytes, an effect that was negated by XAV-939 (β-catenin inhibitor).

Conclusion: These results implied that loganin could exert antidepressant-like effects by improving the gap junctions of astrocytes in the prefrontal cortex and hippocampus, acting through the GSK-3β/β-catenin signaling pathway. The combination of loganin with fluoxetine may provide a faster onset of antidepressant action compared to either treatment alone, highlighting the potential of loganin as a natural adjunct therapy for depression.