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抑郁症是一种严重危及人类身心健康的情感障碍性精神疾病。临床常用抗抑郁药物在一定程度上能够缓解患者的症状,但存在起效缓慢、副作用大等局限性。神经肽是体内重要的生物活性分子,广泛参与了应激反应、睡眠、情绪等过程。近年来,神经肽在抑郁症发病中的作用逐渐引起关注,以神经肽作为分子靶点已经成为抗抑郁药研发的新方向。神经肽三叶因子3(trefoil factor 3,TFF3)分布于海马、杏仁核和下丘脑等脑区,参与焦虑行为的调节。本研究旨在探讨神经肽TFF3的抗抑郁作用,以期为抑郁症发生机制研究和开发新型抗抑郁药物提供实验依据。大鼠强迫游泳实验是经典的行为绝望模型,因其简单、快速、敏感,经常被用于抗抑郁药物的快速筛选。在强迫游泳实验中,单次给予TFF3能显著降低大鼠不动时间,而不影响大鼠自发活动。慢性轻度应激通过长期给予动物厌恶的、不可预见的应激,比较真实的模拟了人类抑郁症的环境因素,使动物表现出与抑郁症患者相似的行为变化,是目前国内外公认的抑郁症模型之一。我们采用连续给予21 d应激,通过糖水偏爱来检测动物的快感缺失以及TFF3的抗抑郁作用。与对照组比较,应激组动物蔗糖偏爱度降低,单次给予TFF3可逆转上述抑郁样行为,提示TFF3在这一模型上具有良好的抗抑郁样作用。此外,单次给予TFF3能显著增加基底外侧杏仁核(BLA)脑区的c-Fos表达,但对CeAc-FOS表达水平无显著影响。最后,BLA微注射PI3K抑制剂LY294002能显著抑制TFF3的抗抑郁作用,表现为LY294002能逆转强迫游泳中TFF3给药大鼠不动时间的降低,LY294002给药本身不改变大鼠强迫游泳的不动时间。TFF3不改变大鼠的攀爬时间,而LY294002给药本身也不显著改变大鼠攀爬时间。本研究结果首次证实了神经肽TFF3具有抗抑郁作用,BLA脑区PI3K信号通路可能介导了TFF3的抗抑郁作用。本研究的开展为抑郁症发病机制研究和开发以神经肽TFF3为靶点的新型抗抑郁药物提供了新的思路。
Depression is a devastating mental disorder that seriously affects human health. Antidepressants commonly used in clinical patients to some extent, can alleviate the symptoms, but there are slow onset, side effects and other limitations. Neuropeptide is an important biologically active molecule in the body and is widely involved in stress response, sleep, mood and other processes. In recent years, the role of neuropeptides in the pathogenesis of depression has gradually attracted the attention of neuropeptides as molecular targets has become the new direction of the development of antidepressants. Neuropeptide trefoil factor 3 (TFF3) is located in brain regions such as hippocampus, amygdala and hypothalamus, and is involved in the regulation of anxiety. This study aimed to investigate the antidepressant effect of neuropeptide TFF3 in order to provide experimental evidence for the study of the mechanism of depression and the development of novel antidepressants. Forced swimming in rats is a classic behavioral despair model, which is often used for the rapid screening of antidepressant drugs because of its simplicity, rapidness and sensitivity. In forced swimming test, single administration of TFF3 can significantly reduce rat immobility time, without affecting spontaneous activity in rats. Chronic Mild Stress By giving animals an unpleasant, unpredictable stress for a long period of time, the more realistic environmental factors that mimic human depression make animals behave similarly to those in patients with depression, and are considered as the most commonly recognized depression One of the disease models. We used 21 consecutive days of stress, and we tested for the loss of pleasure and the anti-depressant effect of TFF3 through glycemic preference. Compared with the control group, the preference of sucrose in stressed animals was decreased. TFF3 alone reversed the above depression-like behavior, suggesting that TFF3 had a good antidepressant-like effect on this model. In addition, single administration of TFF3 significantly increased c-Fos expression in the basolateral amygdala (BLA) brain, but had no significant effect on the expression of CeAc-FOS. Finally, BLA microinjection of PI3K inhibitor LY294002 significantly inhibited the antidepressant effect of TFF3, showing that LY294002 reversed the immobility time of TFF3-administered rats in forced swimming. LY294002 itself did not change the forced swimming of rats time. TFF3 did not change the climbing time in rats, while administration of LY294002 did not significantly alter the climbing time in rats. The results of this study for the first time confirmed that the neuropeptide TFF3 has antidepressant effect, and the PI3K signaling pathway in BLA may mediate the antidepressant effect of TFF3. This study provides a new idea for the study of the pathogenesis of depression and the development of novel antidepressants targeting neuropeptide TFF3.