Departmental Papers (Dental)
Oral Delivery of the P2Y12 Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4−/− Mouse Model of Retinal Degeneration
Date of this Version
Investigative Ophthalmology and Visual Science
PURPOSE. Accumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4 mouse model of Stargardt's retinal degeneration. As treatment with the P2Y12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss. METHODS. Moderate light exposure was used to accelerate photoreceptor loss in albino ABCA4 mice as compared to BALB/c controls. Ticagrelor (0.1%–0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology. RESULTS. Protection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4 mice had increased a-and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor. CONCLUSIONS. Oral treatment with ticagrelor protected photoreceptors in the ABCA4 mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt’s disease and other neurodegenerations associated with lysosomal dysfunction. © 2019 The Authors. All rights reserved.
ABCA4, drug delivery, lysosome, protection, retinal dystrophy, Administration, Oral, Animals, Disease Models, Animal, Electroretinography, Gene Expression Regulation, Lysosome-Associated Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Neoplasm Proteins, Purinergic P2Y Receptor Antagonists, Retinal Degeneration, Retinal Pigment Epithelium, RNA, Ticagrelor, Tomography, Optical Coherence, Treatment Outcome, lipofuscin, lysosome associated membrane protein 1, purinergic P2Y12 receptor, ticagrelor, transcription factor ZEB1, tropicamide, Lamp1 protein, mouse, lysosome associated membrane protein, purinergic P2Y receptor antagonist, RNA, ticagrelor, tumor protein, animal experiment, animal model, animal tissue, Article, cell survival, controlled study, electroretinogram, electroretinography, female, food intake, gene expression, light exposure, lysosome, lysosome storage disease, male, mouse, nerve degeneration, nonhuman, ophthalmoscopy, optical coherence tomography, pH, phenotype, photoreceptor, priority journal, protein expression, retina cell, retina degeneration, retina ganglion cell, retina neovascularization, retinal thickness, RNA isolation, Stargardt disease, animal, Bagg albino mouse, biosynthesis, disease model, drug effect, gene expression regulation, genetics, metabolism, oral drug administration, pathology, pathophysiology, retina degeneration, retinal pigment epithelium, treatment outcome
Lu, W., Campagno, K. E., Tso, H., Cenaj, A., Laties, A. M., Carlsson, L. G., & Mitchell, C. H. (2019). Oral Delivery of the P2Y12 Receptor Antagonist Ticagrelor Prevents Loss of Photoreceptors in an ABCA4−/− Mouse Model of Retinal Degeneration. Investigative Ophthalmology and Visual Science, 60 (8), 3046-3053. http://dx.doi.org/10.1167/iovs.19-27241
Date Posted: 10 February 2023
This document has been peer reviewed.