Survey of Dopamine Receptor D2 Antagonists as Retinal Antifibrotics.
Ashley Y GaoMadison G WhaleyNamita SarafSophie J BakriAndrew J HaakPublished in: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (2024)
Purpose: To evaluate the potency and efficacy of a library of dopamine receptor D2 (D2R) antagonists in the mitigation of fibrotic activation in retinal pigment epithelial (RPE) cells. Methods: ARPE-19 cells were cultured and treated with methotrexate or 27 district D2R antagonists using a fibronectin deposition assay. The most potent compounds were then further assessed in assays measuring cellular proliferation, cellular migration, and profibrotic gene expression. Results: The previously established antifibrotic D2R antagonist loxapine exerted a robust and dose-dependent inhibition of fibronectin deposition, whereas methotrexate exerted minimal inhibition. The most potent D2R antagonist identified, fluphenazine, effectively blocked in vitro models of fibrosis at 300-1,000 nM concentrations. Conclusions: Here we found multiple FDA-approved D2R antagonists that potently block RPE cell fibrogenesis. These findings further support the potential of D2R antagonism as a potential therapeutic for retinal fibrotic disease.
Keyphrases
- induced apoptosis
- gene expression
- cell cycle arrest
- optical coherence tomography
- diabetic retinopathy
- systemic sclerosis
- high dose
- high throughput
- idiopathic pulmonary fibrosis
- dna methylation
- stem cells
- climate change
- south africa
- photodynamic therapy
- oxidative stress
- cross sectional
- metabolic syndrome
- cell therapy
- optic nerve
- bone marrow
- mesenchymal stem cells
- cell proliferation
- risk assessment
- human health
- pulmonary fibrosis