MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish
Chemistry & Biology (2015) Volume 22, Issue 10, p1335–1346
Lundegaard et al. identify therapeutic potential for anti-cancer MEK-inhibitors to treat anxiety-like cAMP-mediated behaviors in zebrafish. Targeting cAMP-MAPK cross-talk pathways broadens the range of therapeutic targets for mental health disorders. This work illustrates the importance of whole-animal phenotypic screening in anxiety drug discovery and repurposing.
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.
Read full article here