Wang Xue, Zhu Liyun, Hu Jian, Guo Ruili, Ye Shasha, Liu Fei, Wang Dongxue, Zhao Yeli, Hu Aiping, Wang Xiaojie, Guo Kaiming, Lin Li
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou, China.
Front Pharmacol. 2020 Feb 28;11:154. doi: 10.3389/fphar.2020.00154. eCollection 2020.
Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)-induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia . The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-κB (NF-κB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial expression of proinflammatory cytokines through NF-κB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment.
重度抑郁症是一种严重的神经精神疾病，复发率和死亡率都很高。许多研究支持炎症过程在抑郁症病因中起核心作用。成纤维细胞生长因子21（FGF21）是成纤维细胞生长因子（FGFs）家族的一员，可调节多种药理活性，包括能量代谢、葡萄糖和脂质代谢以及胰岛素敏感性。此外，最近的研究表明，给予作为代谢功能调节剂的FGF21对情绪稳定剂有治疗作用，这表明FGF21可能是情绪反应的常见调节剂。然而，很少有研究强调FGF21对脂多糖（LPS）诱导的小鼠的抗抑郁作用，FGF21在抑郁症中的抗炎机制尚未阐明。本研究的目的是确定重组人FGF21（rhFGF21）的抗抑郁作用。在LPS诱导的小鼠模型和原代小胶质细胞中研究了rhFGF21对抑郁样行为和炎症信号通路的影响。本研究表明，LPS诱导小鼠出现抑郁样行为，上调促炎细胞因子，激活小鼠海马中的小胶质细胞，并激活原代小胶质细胞中的炎症反应，而rhFGF21预处理可显著改善抑郁样行为缺陷，如旷场试验（OFT）中总行进距离和站立次数增加，尾悬架试验（TST）和强迫游泳试验（FST）中不动时间减少所示。此外，rhFGF21明显抑制促炎细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的表达水平，并抑制小胶质细胞激活和核因子-κB（NF-κB）信号通路。此外，rhFGF21与成纤维细胞生长因子受体1（FGFR1）抑制剂PD173074联合给药显著逆转了这些保护作用，表明rhFGF21的抗抑郁作用是通过FGFR1激活实现的。综上所述，本研究结果首次表明，外源性rhFGF21通过抑制小胶质细胞促炎细胞因子的表达和NF-κB抑制来改善LPS诱导的抑郁样行为。这一新发现表明rhFGF21是抑郁症治疗的新候选药物。
