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

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-26 DOI:10.1038/s41401-025-01506-w
Shao-Qi Zhang, Qiao Deng, Cheng Tian, Huan-Huan Zhao, Li-Ying Yang, Xin-Wei Cheng, Guo-Ping Wang, Dong Liu
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引用次数: 0

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.

木香内酯通过抑制小胶质细胞Akt/mTOR/NF-κB通路,使小鼠抑郁模型中的神经炎症正常化并改善神经发生缺陷。
神经炎症在重度抑郁症的发病机制中起着至关重要的作用。临床前研究表明,抗炎药的潜力,特别是COS,与抗抑郁作用相关。在本研究中,我们探讨了COS抗抑郁作用的分子机制。慢性约束应激(CRS)诱导雄性小鼠。小鼠分别注射COS (5 μM,每侧1 μL)或COS (20 mg/kg, i.p),连续1周。我们发现,通过这两种途径给药COS可显著改善crs暴露小鼠的抑郁样行为。此外,COS通过减轻小胶质细胞来源的神经炎症,显著改善小鼠慢性应激诱导的成年海马神经发生缺陷。我们发现,COS (5 μM)通过抑制小胶质细胞Akt/mTOR/NF-κB通路,在lps处理的BV2细胞中发挥抗神经炎作用;在crs暴露小鼠中,COS的促神经原性作用需要mTOR/NF-κB/IL-1β通路失活。我们的研究结果揭示了COS的抗抑郁机制,即使神经炎症正常化以改善神经发生缺陷,支持抗炎药作为抑郁症的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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