TY - JOUR
T1 - MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish
AU - Lundegaard, Pia R.
AU - Anastasaki, Corina
AU - Grant, Nicola J.
AU - Sillito, Rowland R
AU - Zich, Judith
AU - Zeng, Zhiqiang
AU - Paranthaman, Karthika
AU - Larsen, Anders Peter
AU - Armstrong, J. Douglas
AU - Porteous, David J.
AU - Patton, E. Elizabeth
N1 - Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
PY - 2015/10/22
Y1 - 2015/10/22
N2 - Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.
AB - Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP.
U2 - 10.1016/j.chembiol.2015.08.010
DO - 10.1016/j.chembiol.2015.08.010
M3 - Journal article
C2 - 26388333
SN - 1074-5521
VL - 22
SP - 1335
EP - 1346
JO - Chemistry & Biology
JF - Chemistry & Biology
IS - 10
ER -
