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.
Eur J Pharmacol. 2020 Aug 15;881:173192. doi: 10.1016/j.ejphar.2020.173192. Epub 2020 May 12.
Depressive disorders are both prevalent and debilitating, and a proportion of patients have treatment resistance to classic antidepressants. Recent evidence has implicated the intracellular WNT signaling pathway as having a key role in the pathogenesis of major depressive disorder. In the present study, we investigated the role of β-catenin and transcription factor-4 (TCF4) in the depression-like and anxiety-like behaviors exhibited by mice exposed to maternal separation, or chronic mild stress. Both rodent models of childhood and adulthood stress showed depression and anxiety-like behaviors. During the last three weeks of medication, we applied AMBMP (2-Amino-4-[3,4- (methylenedioxy)benzylamino]-6-(3-methoxyphenyl)pyrimidine) to the maternal separation and chronic stress model for the first time. The drug alleviated the depression-like index in saccharin preference test (SPT) and forced swim test (FST), and anxiety-like index in open field test (OFT) and elevated-plus maze (EPM), and reversed the disruption of β-catenin and TCF4 in stressed mice by upregulating the WNT pathway specifically. Therefore, the WNT pathway may be involved in the mediation of patient recovery and could be a target for novel antidepressants.
抑郁障碍普遍存在且使人虚弱，一部分患者对经典抗抑郁药有治疗抵抗。最近的证据表明，细胞内 WNT 信号通路在重度抑郁症的发病机制中具有关键作用。在本研究中，我们研究了 β-连环蛋白和转录因子 4（TCF4）在经历母体分离或慢性轻度应激的小鼠中表现出的抑郁样和焦虑样行为中的作用。儿童和成年期应激的这两种啮齿动物模型都表现出抑郁和焦虑样行为。在药物治疗的最后三周，我们首次将 AMBMP（2-氨基-4-[3,4-（亚甲二氧基）苄基氨基]-6-（3-甲氧基苯基）嘧啶）应用于母体分离和慢性应激模型。该药物缓解了蔗糖偏好测试（SPT）和强迫游泳测试（FST）中的抑郁样指数，以及开阔场测试（OFT）和高架十字迷宫测试（EPM）中的焦虑样指数，并通过特异性地上调 WNT 通路来逆转应激小鼠中 β-连环蛋白和 TCF4 的破坏。因此，WNT 通路可能参与了患者的恢复过程，可能成为新型抗抑郁药的作用靶点。
