Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
Department of Psychiatry, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
Pharmacol Biochem Behav. 2018 Jun;169:59-66. doi: 10.1016/j.pbb.2018.04.005. Epub 2018 Apr 21.
Nuclear factor-kappa B (NF-κB), which is reported to play an important role in the pathogenesis of depression, also has a central role in the genesis and progression of inflammation. Here, we have targeted the nuclear translocation of NF-κB using 4-methyl-N1-(3-phenyl-propyl)-benzene-1,2-diamine (JSH-23) to elucidate its role in depression. We investigated the antidepressant-like effects of JSH-23 in the chronic mild stress (CMS) mouse model, which is a valid, reasonably reliable, and useful model of depression. The antidepressant-like effects of JSH-23 were evaluated using the sucrose preference test (SPT) and the forced swimming test (FST). We also assessed inflammatory markers [interleukin (IL)-6 and tumor necrosis factor-α (TNF-α)] and components of antioxidant defense [superoxide dismutase (SOD) and nuclear factor erythroid-2-related factor 2 (Nrf 2)] in the hippocampus. Fluoxetine, a classical antidepressant, was used in this study as a positive control. Administration of JSH-23 significantly prevented the decreased sucrose preference in the SPT and prevented the increased immobility time in the FST caused by CMS, but had no effect on locomotor activity. Expression of NF-κB p65 protein in the hippocampus was decreased, and elevated levels of IL-6 and TNF-α were reduced, after JSH-23 administration. In addition to its anti-inflammatory effect, JSH-23 treatment increased the expression of SOD and Nrf 2 in the hippocampus, suggesting that it strengthens antioxidant defense. The current study demonstrated that inhibiting the NF-κB signaling cascade using JSH-23 prevented depressive-like behaviors by decreasing inflammation and improving antioxidant defense in the hippocampus. We concluded that NF-κB activation plays an important role in the pathophysiology of depression and that targeting NF-κB signaling may provide a novel and effective therapy for depression. Additional preclinical studies and clinical trials are, however, needed to further elucidate the effects of this therapeutic strategy.
核因子-κB（NF-κB）被报道在抑郁症的发病机制中发挥重要作用，它在炎症的发生和进展中也起着核心作用。在这里，我们使用 4-甲基-N1-（3-苯基-丙基）-苯-1,2-二胺（JSH-23）靶向 NF-κB 的核易位，以阐明其在抑郁症中的作用。我们在慢性轻度应激（CMS）小鼠模型中研究了 JSH-23 的抗抑郁样作用，该模型是一种有效的、合理可靠的、有用的抑郁症模型。使用蔗糖偏好测试（SPT）和强迫游泳测试（FST）评估 JSH-23 的抗抑郁样作用。我们还评估了海马中的炎症标志物[白细胞介素（IL）-6 和肿瘤坏死因子-α（TNF-α）]和抗氧化防御成分[超氧化物歧化酶（SOD）和核因子红细胞 2 相关因子 2（Nrf2）]。在这项研究中，氟西汀，一种经典的抗抑郁药，被用作阳性对照。JSH-23 的给药显著预防了 SPT 中蔗糖偏好的降低，并预防了 CMS 引起的 FST 中不动时间的增加，但对运动活性没有影响。JSH-23 给药后，海马中 NF-κB p65 蛋白的表达减少，升高的 IL-6 和 TNF-α 水平降低。除了抗炎作用外，JSH-23 治疗还增加了海马中 SOD 和 Nrf2 的表达，表明它增强了抗氧化防御。本研究表明，使用 JSH-23 抑制 NF-κB 信号级联反应通过降低海马中的炎症和改善抗氧化防御来预防抑郁样行为。我们得出结论，NF-κB 激活在抑郁症的病理生理学中起着重要作用，针对 NF-κB 信号可能为抑郁症提供一种新的有效治疗方法。然而，需要进一步的临床前研究和临床试验来进一步阐明这种治疗策略的效果。
