Purchase this article with an account.
Yu Chen, Kiichiro Okano, Tadao Maeda, Vishal Chauhan, Marcin Golczak, Akiko Maeda, Krzysztof Palczewski; Mechanism Of All-Trans-retinal Toxicity: Implications For Stargardt’S Disease And Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6469.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Compromised clearance of all-trans-retinal (atRAL), a component of the retinoid cycle, increases the susceptibility of mouse retina to acute light-induced photoreceptor degeneration. Abca4_/_Rdh8_/_ mice featuring defective atRAL clearance were used to examine the underlying molecular mechanism(s) because bright light exposure causes severe photoreceptor degeneration in these animals.
Various pharmacological agents were tested and evaluated using morphological, biochemical and functional approaches in Abca4_/_Rdh8_/_ mouse model.
Bright light exposure of Abca4-/-Rdh8-/- mice increased atRAL levels in the retina that induced rapid NADPH oxidase-mediated overproduction of intracellular reactive oxygen species (ROS). Moreover, such ROS generation was inhibited by blocking phospholipase C and IP3-induced Ca2+ release, indicating that activation occurs upstream of NADPH oxidase-mediated ROS generation. Because multiple upstream G protein-coupled receptors (GPCRs) can activate phospholipase C, we then tested the effects of antagonists of serotonin 2A (5-HT2AR) and M3-muscarinic (M3R) receptors and found they both protected Abca4-/-Rdh8-/- mouse retinas from light-induced degeneration.
A cascade of signaling events appears to mediate the toxicity of atRAL in light-induced photoreceptor degeneration of Abca4-/-Rdh8-/- mice. A similar mechanism may be operative in human Stargardt’s disease and age-related macular degeneration.
This PDF is available to Subscribers Only