D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration
Open Access
- 3 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Signal Transduction and Targeted Therapy
- Vol. 5 (1), 1-12
- https://doi.org/10.1038/s41392-020-0122-1
Abstract
Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.This publication has 50 references indexed in Scilit:
- The Hallmarks of AgingCell, 2013
- The Role of Metallothionein in Oxidative StressInternational Journal of Molecular Sciences, 2013
- A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium DevelopmentPLoS Genetics, 2012
- Tricyclodecan-9-yl-Xanthogenate (D609) Mechanism of Actions: A Mini-Review of LiteratureNeurochemical Research, 2011
- mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in miceJCI Insight, 2011
- Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer CellsCancer Research, 2010
- The Retinal Pigment Epithelium: Something More than a Constituent of the Blood-Retinal Barrier—Implications for the Pathogenesis of Diabetic RetinopathyJournal of Biomedicine and Biotechnology, 2010
- Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epitheliumGenes & Development, 2008
- Podocyte-Specific Overexpression of the Antioxidant Metallothionein Reduces Diabetic NephropathyJournal of the American Society of Nephrology, 2008
- In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disordersFree Radical Biology & Medicine, 2006