March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Mechanism Of All-Trans-retinal Toxicity: Implications For Stargardt’S Disease And Age-related Macular Degeneration
Author Affiliations & Notes
  • Yu Chen
    Pharmacology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Kiichiro Okano
    Pharmacology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Tadao Maeda
    Pharmacology,
    Ophthalmology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Vishal Chauhan
    Pharmacology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
    Ophthalmology, Case Western Reserve University, Cleveland, Ohio
  • Marcin Golczak
    Pharmacology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Akiko Maeda
    Pharmacology,
    Ophthalmology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Krzysztof Palczewski
    Pharmacology,
    Case Western Reserve University School of Medicine, Cleveland, Ohio
  • Footnotes
    Commercial Relationships  Yu Chen, None; Kiichiro Okano, None; Tadao Maeda, None; Vishal Chauhan, None; Marcin Golczak, None; Akiko Maeda, None; Krzysztof Palczewski, None
  • Footnotes
    Support  EY009339, EY021126, EY019031, EY019880 and P30 EY11373 from the National Institutes of Health, the Research to Prevent Blindness Foundation, and the Ohio Lions Eye Research Foundation.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6469. doi:
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      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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : Various pharmacological agents were tested and evaluated using morphological, biochemical and functional approaches in Abca4_/_Rdh8_/_ mouse model.

Results: : 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.

Conclusions: : 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.

Keywords: age-related macular degeneration • retinal degenerations: cell biology • photoreceptors 
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