KCNQ channel openers reverse depressive symptoms via an active resilience mechanism

Allyson K. Friedman, Barbara Juarez, Stacy M. Ku, Hongxing Zhang, Rhodora C. Calizo, Jessica J. Walsh, Dipesh Chaudhury, Song Zhang, Angel Hawkins, David M. Dietz, James W. Murrough, Maria Ribadeneira, Erik H. Wong, Rachael L. Neve and Ming-Hu Han ()
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Allyson K. Friedman: Icahn School of Medicine at Mount Sinai
Barbara Juarez: Icahn School of Medicine at Mount Sinai
Stacy M. Ku: Icahn School of Medicine at Mount Sinai
Hongxing Zhang: Icahn School of Medicine at Mount Sinai
Rhodora C. Calizo: Icahn School of Medicine at Mount Sinai
Jessica J. Walsh: Icahn School of Medicine at Mount Sinai
Dipesh Chaudhury: Icahn School of Medicine at Mount Sinai
Song Zhang: Icahn School of Medicine at Mount Sinai
Angel Hawkins: Icahn School of Medicine at Mount Sinai
David M. Dietz: Icahn School of Medicine at Mount Sinai
James W. Murrough: Icahn School of Medicine at Mount Sinai
Maria Ribadeneira: CNS Pain Innovative Medicine Unit, AstraZeneca Pharmaceuticals
Erik H. Wong: CNS Pain Innovative Medicine Unit, AstraZeneca Pharmaceuticals
Rachael L. Neve: McGovern Institute for Brain Research, Massachusetts Institute of Technology
Ming-Hu Han: Icahn School of Medicine at Mount Sinai

Nature Communications, 2016, vol. 7, issue 1, 1-7

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11671

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