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Published on: December 5, 2013
MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish
Pia R Lundegaard1, Corina Anastasaki2, Nicola J Grant3
1MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Department of Biomedical Sciences, Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, 2200 Copenhagen, Denmark.
Abstract:
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.
Insights
Researchers repurposed anti-cancer MEK inhibitors as novel anxiolytics. These drugs effectively reduced anxiety-like behaviors in zebrafish by targeting the phosphodiesterase-cyclic AMP (PDE-cAMP) pathway, offering a new therapeutic strategy for anxiety disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) signaling is linked to anxiety disorders.
- Current anxiety treatments focus on neuronal excitability, not PDE-cAMP pathways.
Purpose of the Study:
- To investigate the novel repositioning of anti-cancer MEK inhibitors as anxiolytics.
- To explore the PDE-cAMP pathway's role in anxiety-like behaviors using a zebrafish model.
Main Methods:
- Utilized a zebrafish model to assess anxiety-like behaviors.
- Conducted small-molecule screening to identify compounds affecting PDE-cAMP-mediated anxiety.
- Investigated the RAS-MAPK signaling pathway's involvement.
Main Results:
- PDE inhibitors and adenylate cyclase activators induced anxiety behaviors in zebrafish.
- MEK inhibitors significantly suppressed cAMP-induced anxiety behaviors in larvae and adult zebrafish.
- Identified crosstalk between cAMP and the RAS-MAPK pathway in anxiety.
Conclusions:
- MEK inhibitors show potential as anxiolytics by stabilizing behavior in the context of increased cAMP.
- Targeting crosstalk signaling pathways represents a promising strategy for mental health disorders.
- Repositioning anti-cancer drugs offers novel therapeutic avenues for anxiety.
