MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish
| Autor: | Pia R. Lundegaard, Anders Peter Larsen, David J. Porteous, Rowland R. Sillito, Nicola J. Grant, J. Douglas Armstrong, Karthika Paranthaman, E. Elizabeth Patton, Zhiqiang Zeng, Corina Anastasaki, Judith Zich |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.drug_class
Clinical Biochemistry Adenylate kinase Pharmacology Anxiety Biochemistry Anxiolytic Article 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Cyclic AMP Animals Humans Enzyme Inhibitors Molecular Biology Zebrafish 030304 developmental biology 0303 health sciences biology MAP kinase kinase kinase Behavior Animal fungi Phosphodiesterase General Medicine biology.organism_classification MAP Kinase Kinase Kinases 3. Good health Crosstalk (biology) Disease Models Animal Molecular Medicine Signal transduction medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Chemistry & Biology Lundegaard, P R, Anastasaki, C, Grant, N J, Sillito, R R, Zich, J, Zeng, Z, Paranthaman, K, Larsen, A P, Armstrong, J D, Porteous, D J & Patton, E E 2015, ' MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish ', Chemistry and Biology . https://doi.org/10.1016/j.chembiol.2015.08.010 |
| ISSN: | 1879-1301 |
| DOI: | 10.1016/j.chembiol.2015.08.010 |
| Popis: | Summary 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. Graphical Abstract Highlights • PDE4 blockade/AC activation causes novel anxiety-like behaviors in zebrafish • Small-molecule screen identifies MEK inhibitors as suppressors of cAMP anxiety • Increased cAMP stimulates crosstalk to RAS-MAPK pathway activity • New therapeutic potential for MEK inhibitors to treat cAMP-mediated anxiety Lundegaard et al. identify therapeutic potential for anti-cancer MEK inhibitors to treat anxiety-like cAMP-mediated behaviors in zebrafish. Targeting cAMP-MAPK crosstalk 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. |
| Databáze: | OpenAIRE |
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