CPD47, a novel GSK-3β inhibitor, demonstrates antidepressant-like effects via the GSK-3β/β-catenin signaling pathway: Involvement of neurogenesis promotion and neuroinflammation inhibition.

Abstract

The GSK-3β/β-catenin signaling axis is critically involved in the pathogenesis of depression. Targeted inhibition of GSK-3β to activate β-catenin signaling may provide a promising depression therapy. The novel GSK-3β inhibitor compound 47 (CPD47) has exhibited therapeutic promise in neurodegenerative disorders such as Alzheimer's disease, but its potential antidepressant effects and underlying mechanisms remain to be elucidated. This study assessed CPD47's protective effects against PC12 cell injury induced by corticosterone (CORT) and its antidepressant-like activity in rats exposed to chronic unpredictable mild stress (CUMS), with a special focus on the mechanisms involving the regulation of the GSK-3β/β-catenin signaling pathway. In this research, CPD47 treatment attenuated CORT-induced neurotoxicity in PC12 cells, as indicated by increased viability, decreased apoptosis, reduced oxidative stress, and suppressed inflammatory responses. In vivo, administration of CPD47 substantially alleviated depressive-like behaviors in CUMS rats, as indicated by behavioral improvements in sucrose preference, forced swim, sucrose splash, and open field tests. Additionally, CPD47 ameliorated hippocampal pathological damage and promoted hippocampal neurogenesis in CUMS rats. Notably, CPD47 markedly mitigated neuroinflammation in the hippocampus of CUMS rats. Mechanistically, CPD47 significantly inhibited GSK-3β activity and activated β-catenin signaling both in vitro and in vivo, with upregulated p-GSK-3β (Ser9) and β-catenin expression and decreased p-β-catenin. Importantly, GSK-3β overexpression abolished CPD47's benefits in CORT-stimulated PC12 cells, providing further evidence that GSK-3β is its crucial molecular target. Collectively, our findings indicate that CPD47 produces potent antidepressant-like effects through modulation of the GSK-3β/β-catenin axis, highlighting its promise as a candidate for depression therapy.