Department of Physiology, Shandong University, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong Province 250012, PR China.
Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwuweiqi Road 423#, Jinan, Shandong Province 250012, PR China.
Brain Behav Immun. 2019 Nov;82:106-121. doi: 10.1016/j.bbi.2019.08.002. Epub 2019 Aug 5.
Neuronal injury within specific brain regions is considered a critical risk factor in the pathophysiology of depression. However, the underlying mechanisms of this process, and thus the potential for development of novel therapeutic strategies in the treatment of depression, remain largely unknown. Here, we report that Il-6 protects against neuronal anomalies related with depression, in part, by suppressing oxidative stress and consequent autophagic and apoptotic hyperactivity. Specifically, we show that IL-6 is downregulated within the CA1 hippocampus in two animal models of depression and upregulated by antidepressants. Increasing levels of IL-6 in the CA1 region result in pleiotropic protective actions including reductions in oxidative stress and modulation of autophagy, anti-immuno-inflammatory activation and anti-apoptotic effects in CA1 neurons, all of which are associated with the rescue of depression-like behaviors. In contrast, IL-6 downregulation exacerbates neuronal anomalies within the CA1 region and facilitates the genesis of depression phenotypes in rats. Interestingly, in addition to attenuating oxidative damage, the antioxidant, N-acetylcysteine (NAC), is also associated with significantly decreased neuronal deficits and the display of depressive behaviors in rats. These results suggest that IL-6 may exert neuroprotection within CA1 neurons via pleiotropic mechanisms and may serve as a potential therapeutic target for the treatment of depression.
特定脑区的神经元损伤被认为是抑郁症病理生理学中的一个关键风险因素。然而，这一过程的潜在机制，以及开发治疗抑郁症的新治疗策略的潜力，在很大程度上仍然未知。在这里，我们报告说，IL-6 通过抑制氧化应激和随后的自噬和细胞凋亡过度活跃，部分保护与抑郁相关的神经元异常。具体来说，我们表明，两种抑郁症动物模型的 CA1 海马体中的 IL-6 下调，而抗抑郁药可上调其表达。增加 CA1 区的 IL-6 水平会导致多种保护作用，包括减少氧化应激、调节自噬、抑制 CA1 神经元的免疫炎症激活和抗细胞凋亡作用，所有这些都与挽救抑郁样行为有关。相比之下，IL-6 的下调会加剧 CA1 区的神经元异常，并促进大鼠出现抑郁表型。有趣的是，除了减轻氧化损伤外，抗氧化剂 N-乙酰半胱氨酸（NAC）还与大鼠神经元缺陷的显著减少和抑郁行为的表现显著相关。这些结果表明，IL-6 可能通过多种机制在 CA1 神经元中发挥神经保护作用，并可能成为治疗抑郁症的潜在治疗靶点。
