KCNQ channel openers reverse depressive symptoms via an active resilience mechanism.
KCNQ channel openers reverse depressive symptoms via an active resilience mechanism.
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DOI：
10.1038/ncomms11671
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发表时间：
2016-05-24
影响因子：
16.6
通讯作者：
Han MH
中科院分区：
文献类型：
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作者：
Friedman AK;Juarez B;Ku SM;Zhang H;Calizo RC;Walsh JJ;Chaudhury D;Zhang S;Hawkins A;Dietz DM;Murrough JW;Ribadeneira M;Wong EH;Neve RL;Han MH
严重抑郁障碍是全球残疾的主要原因，只有不到一半的患者通过目前的抗抑郁药物获得缓解，因此开发更有效的治疗方法势在必行。一个新的治疗方向正在出现，因为人们越来越多地理解自然的弹性是一种积极的压力应对过程。众所周知，腹侧被盖区(VTA)的钾(K+)通道是一种活跃的弹性介质。然而，还没有确定可用来增强主动弹性机制的可用药靶点。在抑郁症的慢性社会失败应激模型中，我们报道了KCNQ型K+通道开放剂，包括FDA批准的药物雷替加宾(Ezogabine)，显示出抗抑郁的效果。我们证明，KCNQ通道在VTA多巴胺能神经元中的过度表达以及局部输注或全身给药可使神经元的过度活动和抑郁行为正常化。这些发现确定KCNQ是概念上新型抗抑郁药物的靶点，这些药物通过增强主动弹性机制发挥作用。众所周知，腹侧被盖区的钾通道可以调节对应激诱导的抑郁的弹性。在这里，作者展示了KCNQ3通道在VTA多巴胺能神经元中的过度表达或用KCNQ通道开放剂治疗可以使小鼠模型中的抑郁行为正常化。
Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K+) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K+ channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms. Potassium channels in the ventral tegmental area are known to regulate resilience against stress-induced depression. Here, the authors show over expression of KCNQ3 channels in VTA dopaminergic neurons or treatment with KCNQ channel openers normalizes depressive behaviours in mouse models.