1. Ritanserin, a potent serotonin 2A receptor antagonist, represses MEK/ERK signalling pathway to restore PAX6 production and function in aniridia-like cellular model.
- Author
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Oved K, Zennaro L, Dorot O, Zerbib J, Frank E, Roux LN, Bremond-Gignac D, Pichinuk E, and Aberdam D
- Subjects
- Aniridia drug therapy, Aniridia genetics, Aniridia metabolism, Aniridia pathology, Cell Line, Cell Movement drug effects, Cell Proliferation drug effects, Drug Repositioning methods, Epithelium, Corneal drug effects, Epithelium, Corneal metabolism, Epithelium, Corneal pathology, Gene Expression Regulation, HEK293 Cells, Haploinsufficiency, Humans, Limbus Corneae drug effects, Limbus Corneae metabolism, Limbus Corneae pathology, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 metabolism, Models, Biological, PAX6 Transcription Factor agonists, PAX6 Transcription Factor metabolism, Receptor, Serotonin, 5-HT2A genetics, Receptor, Serotonin, 5-HT2A metabolism, Signal Transduction drug effects, Stem Cells metabolism, Stem Cells pathology, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 3 genetics, Ophthalmic Solutions pharmacology, PAX6 Transcription Factor genetics, Ritanserin pharmacology, Serotonin Antagonists pharmacology, Stem Cells drug effects
- Abstract
Aniridia is a panocular inherited rare eye disease linked to heterozygous mutations on the PAX6 gene, which fail to properly produce sufficient protein essential for normal eye development and function. Most of the patients suffer from aniridia-related keratopathy, a progressive opacification of the cornea. There is no effective treatment for this blinding disease. Here we screen for small compounds and identified Ritanserin, a serotonin 2A receptor antagonist, that can rescue PAX6 haploinsufficiency of mutant limbal cells, defective cell migration and PAX6-target gene expression. We further demonstrated that Ritanserin activates PAX6 production through the selective inactivation of the MEK/ERK signaling pathway. Our data strongly suggest that repurposing this therapeutic molecule could be effective in preventing or treating existing blindness by restoring corneal transparency., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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