四氢姜黄素通过调控SIRT1/NF-κB通路改善神经炎症与神经营养平衡缓解慢性束缚应激小鼠的抑郁样行为

Tetrahydrocurcumin ameliorates depression-like behaviors in chronic restraint stress mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF-κB pathway

摘要

目的 探讨四氢姜黄素（THC）是否通过调控SIRT1/NF-κB通路改善神经炎症和神经营养平衡，从而缓解小鼠抑郁样行为。 方法 采用慢性束缚应激（CRS）建立小鼠抑郁模型。小鼠接受THC（2.5、5、10 mg·kg^-1·d^-1）或舍曲林（10 mg·kg^-1·d^-1）治疗21 d。通过旷场实验、高架十字迷宫、悬尾实验和强迫游泳实验评小鼠估焦虑和抑郁样行为。采用ELISA、Western blotting和免疫组化检测小鼠血清和海马组织中SIRT1、p-NF-κB/NF-κB、炎症因子（TNF-α、iNOS）和神经营养因子（BDNF、GDNF、TGF-β1）水平。通过免疫荧光分析海马CA3区小胶质细胞激活标志物（Iba1）和SIRT1表达。体外实验中，使用脂多糖（LPS）刺激BV2小胶质细胞，THC单独或联合SIRT1抑制剂EX-527对细胞进行预处理，以验证通路机制。 结果 THC治疗显著缓解了CRS诱导的小鼠焦虑和抑郁样行为，促进小鼠体质量增长。THC降低了CRS小鼠血清和海马中TNF-α与iNOS水平，同时提升SIRT1、BDNF、GDNF和TGF-β1表达。THC抑制了CRS小鼠海马组织中NF-κB活化， 减少海马CA3区中Iba1的表达和 Iba1⁺/SIRT1⁺细胞比例，增加SIRT1表达。体外实验显示，THC减轻LPS诱导的BV2细胞NF-κB活化，降低TNF-α和iNOS表达，促进SIRT1、BDNF、GDNF和TGF-β1表达，这些效应可被EX-527有效阻断。 结论 THC在CRS小鼠中发挥显著的抗抑郁样作用，其机制可能是通过激活SIRT1以抑制NF-κB介导的神经炎症并恢复神经营养因子表达，提示SIRT1/NF-κB通路是THC发挥抗抑郁作用的关键机制。

Abstract

Objective To investigate whether tetrahydrocurcumin (THC) ameliorates depression-like behaviors in mice by modulating neuroinflammation and neurotrophic balance via the SIRT1/NF‑κB pathway. Methods A mouse model of depression was established using chronic restraint stress (CRS). The mice were treated with THC (2.5, 5, or 10 mg/k) or sertraline (10 mg/kg) on a daily basis for 21 consecutive days. Anxiety- and depression-like behaviors of the mice were assessed using open field, elevated plus maze, tail suspension, and forced swimming tests. Serum levels and hippocampal expression levels of SIRT1, p-NF-κB/NF-κB, inflammatory factors (TNF-α and iNOS), and neurotrophic factors (BDNF, GDNF, and TGF-β1) were measured using ELISA, Western blotting, or immunohistochemistry. The expression levels of hippocampal CA3 microglial activation marker (Iba1) and silent information regulator 1 (SIRT1) were analyzed using immunofluorescence staining. In the in vitro experiment, BV2 microglial cells were stimulated with lipopolysaccharide (LPS) and treated with THC with or without the SIRT1 inhibitor EX-527 for validating the pathway mediating the effect of THC. Results THC treatment significantly alleviated CRS-induced anxiety- and depression-like behaviors and increased body weight gain of the mice. THC obviously reduced serum and hippocampal levels of TNF-α and iNOS, increased the expression levels of SIRT1, BDNF, GDNF, and TGF-β1, and inhibited NF‑κB activation in the hippocampus. The THC-treated mice showed significantly reduced Iba1 expression and Iba1⁺/SIRT1⁺ cells and increased SIRT1 expression in the hippocampal CA3 region. In cultured BV2 cells, THC effectively attenuated LPS-induced NF-κB activation, lowered expressions of TNF-α and iNOS, and promoted SIRT1, BDNF, GDNF, and TGF-β1 expressions; these effects were obviously blocked by treatment with EX-527, confirming SIRT1 dependence of the effect of THC. Conclusion THC produces significant antidepressant-like effects in CRS mice likely by activating SIRT1 to suppress NF‑κB-mediated neuroinflammation and restore neurotrophic factor expressions. These findings highlight the SIRT1/NF-κB pathway as a key mechanism mediating the therapeutic effect of THC against depression.

关键词

抑郁症 / 慢性束缚应激 / 四氢姜黄素 / 沉默信息调节因子1 / 核因子κB / 神经炎症 / 神经营养

Key words

depression / chronic restraint stress / tetrahydrocurcumin / silent information regulator 1 / nuclear factor kappa-B / neuroinflammation / neurotrophy

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