2. Academic Validation
  3. Costunolide normalizes neuroinflammation and improves neurogenesis deficits in a mouse model of depression through inhibiting microglial Akt/mTOR/NF-κB pathway

Costunolide normalizes neuroinflammation and improves neurogenesis deficits in a mouse model of depression through inhibiting microglial Akt/mTOR/NF-κB pathway

  • Acta Pharmacol Sin. 2025 Feb 26. doi: 10.1038/s41401-025-01506-w.
Shao-Qi Zhang # 1 2,  Qiao Deng # 3,  Cheng Tian # 3,  Huan-Huan Zhao 4,  Li-Ying Yang 2,  Xin-Wei Cheng 3,  Guo-Ping Wang 5 6,  Dong Liu 7
Affiliations

Affiliations

  • 1 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4 Cancer Institute, Xuzhou Medical University, Xuzhou, 221004, China.
  • 5 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wanggp@hust.edu.cn.
  • 6 Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wanggp@hust.edu.cn.
  • 7 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. ld2069@outlook.com.
  • # Contributed equally.
PMID: 40011631 DOI: 10.1038/s41401-025-01506-w
Abstract

Neuroinflammation is crucial for the pathogenesis of major depression. Preclinical studies have shown the potential of anti-inflammatory agents, specifically costunolide (COS), correlate with antidepressant effects. In this study, we investigated the molecular mechanisms underlying the antidepressant actions of COS. Chronic restraint stress (CRS) was induced in male mice. The mice were treated with either intra-DG injection of COS (5 μM, 1 μL per side) or COS (20 mg/kg, i.p.) for 1 week. We showed that administration of COS through the both routes significantly ameliorated the depressive-like behavior in CRS-exposed mice. Furthermore, administration of COS significantly improved chronic stress-induced adult hippocampal neurogenesis deficits in the mice through attenuating microglia-derived neuroinflammation. We demonstrated that COS (5 μM) exerted anti-neuroinflammatory effects in LPS-treated BV2 cells via inhibiting microglial Akt/mTOR/NF-κB pathway; inactivation of mTOR/NF-κB/IL-1β pathway was required for the pro-neurogenic action of COS in CRS-exposed mice. Our results reveal the antidepressant mechanism of COS that is normalizing neuroinflammation to improve neurogenesis deficits, supporting anti-inflammatory agents as a potential therapeutic strategy for depression.

Keywords

chronic stress; costunolide; mTOR; major depression; microglia; neurogenesis.

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