2. Academic Validation
  3. Eupalinolide B alleviates corticosterone-induced PC12 cell injury and improves depression-like behaviors in CUMS rats by regulating the GSK-3β/β-catenin pathway

Eupalinolide B alleviates corticosterone-induced PC12 cell injury and improves depression-like behaviors in CUMS rats by regulating the GSK-3β/β-catenin pathway

  • Biochem Pharmacol. 2025 May:235:116831. doi: 10.1016/j.bcp.2025.116831.
Tian-Tian Wang 1,  Meng-Yuan Zhou 2,  Xue-Na Gong 3,  Yan Huang 2,  Fei-Long Li 2,  Sheng-Long Gu 2,  Man-Yu Zhang 2,  Ling-Ling Li 2,  Ze-Shan Xu 2,  Rong Li 4,  Li Cai 5
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui Province, PR China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei 230032 Anhui Province, PR China.
  • 2 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui Province, PR China.
  • 3 Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei 230032 Anhui Province, PR China.
  • 4 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei 230032 Anhui Province, PR China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230026 Anhui Province, PR China. Electronic address: lirong@ahmu.edu.cn.
  • 5 Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui Province, PR China; Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei 230032 Anhui Province, PR China. Electronic address: caili@ahmu.edu.cn.
PMID: 40021022 DOI: 10.1016/j.bcp.2025.116831
Abstract

Eupalinolide B (EB), a primary bioactive compound isolated from Eupatorium lindleyanum DC., has exhibited various pharmacological properties, such as antitumor, anti-inflammatory, and notably, neuroprotective effects in neurodegenerative diseases. However, the in-depth studies on the antidepressant potential of EB and its underlying mechanisms are still lacking. Herein, we investigated the therapeutic effects of EB on corticosterone (CORT)-induced neurotoxicity in PC12 cells and its antidepressant-like effects in rats subjected to chronic unpredictable mild stress (CUMS). In particular, we focused on the molecular mechanisms related to modulating the GSK-3β/β-catenin pathway. Our findings revealed that EB promoted cell proliferation while decreasing Apoptosis and oxidative stress in CORT-induced PC12 cells. In vivo, EB alleviated the depressive-like behaviors in CUMS rats, as assayed by the sucrose preference test, open field test, and forced swim test. Additionally, EB attenuated the hippocampal pathological damage and increased Ki67- and doublecortin-positive cell numbers in hippocampal dentate gyrus, thus restoring hippocampal neurogenesis in CUMS rats. The binding of EB to GSK-3β was confirmed using molecular docking and cellular thermal shift assays. Overexpression of GSK-3β diminished the therapeutic effects of EB on CORT-induced PC12 cells, further indicating that GSK-3β is the target of EB. Mechanistically, EB hindered GSK-3β activity and thus activated β-catenin signaling in both CORT-induced PC12 cells and CUMS rat hippocampus, as demonstrated by increased p-GSK-3β (Ser9), reduced p-β-catenin, and elevated β-catenin expression. Collectively, this study offers new insights into the antidepressant mechanisms of EB, highlighting its potential as a candidate for depression treatment.

Keywords

Antidepressant; Chronic unpredictable mild stress; Eupalinolide B; GSK-3β/β-catenin pathway; Neurogenesis.

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