Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors induced by chronic social defeat stress and administration of mefloquine in mice
Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors induced by chronic social defeat stress and administration of mefloquine in mice
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内侧前额叶皮层 Pannexin-1 通道功能障碍介导小鼠慢性社交失败压力和甲氟喹给药引起的抑郁样行为
DOI：
10.1016/j.neuropharm.2017.12.004
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发表时间：
2018-07-15
影响因子：
4.7
通讯作者：
Hu, Zhuang-Li
中科院分区：
文献类型：
--
作者：
Ni, Ming;He, Jin-Gang;Hu, Zhuang-Li
甲氟喹（MFQ）是临床上广泛应用于治疗疟疾的药物。除抗疟作用外，已报道MFQ的精神副作用，如抑郁和焦虑。有趣的是，MFQ也被称为广谱泛连接蛋白-1（Panx 1）抑制剂。Panx 1是脑内一种新的间隙连接通道，介导三磷酸腺苷（ATP）的外排。虽然外源性ATP已被称为产生一个潜在的抗抑郁样作用，很少有人知道Panx 1在抑郁症的病理生理学的作用，特别是由管理MFQ诱导的抑郁症。在这里，我们使用慢性社会失败压力（CSDS）模型，发现易感小鼠内侧前额叶皮层（mPFC）中Panx 1的表达和功能下降。此外，用甘珀酸（CBX）（100 mM）或（10）Panx（100 μ M）药理学阻断mPFC中的Panx 1足以诱导小鼠的抑郁样行为并增加对应激的脆弱性，这可以通过ATP（25 μ M）预处理来预防。最后，全身和mPFC内注射MFQ均抑制Panx 1的活性，并诱导阈下社交失败应激小鼠的抑郁样和焦虑行为。事实上，MFQ诱导的行为异常可以通过在mPFC中使用ATP进行预处理来预防。总之，我们的研究表明Panx 1通道在慢性应激和MFQ诱导的抑郁样和焦虑行为中的作用，这可能为MFQ的精神副作用提供了一种新的分子机制。(C)2017爱思唯尔有限公司版权所有
Mefloquine (MFQ) is widely used for the treatment of malaria clinically. Apart from antimalarial effect, psychiatric side effects such as depression and anxiety of MFQ have been reported. Interestingly, MFQ is also known as a broad-spectrum pannexin-1 (Panx1) inhibitor. Panx1 is a new gap junction channel in the brain which mediates efflux of adenosine triphosphate (ATP). Although exogenous ATP has been known to produce a potential antidepressant-like effect, little is known about the role of Panx1 in pathophysiology of depression, especially the depression induced by administration of MFQ. Here, we used the chronic social defeat stress (CSDS) model and found a decrease in the expression and function of Panx1 in the medial prefrontal cortex (mPFC) of susceptible mice. Furthermore, pharmacological blockade of Panx1 in the mPFC with carbenoxolone (CBX) (100 mM) or (10)Panx (100 uM) was sufficient to induce depressive-like behaviors and increase vulnerability to stress in mice, which were prevented by preconditioning with ATP (25 mu M). Finally, systemic and intral-mPFC injection of MFQ both inhibited the activity of Panx1 and induced depressive-like and anxiety behaviors in mice with sub-threshold social defeat stress. Indeed, the behavioral abnormalities induced by MFQ were prevented by preconditioning with ATP in the mPFC. In conclusion, our study demonstrates a role of the Panx1 channel in chronic stress and MFQ-induced depressive-like and anxiety behaviors, which may provide a novel molecular mechanism for psychiatric side effects of MFQ. (C) 2017 Elsevier Ltd. All rights reserved.