Elucidating the Role of Pyridinium bis-Retinoid (A2E) in Retinal Pigment Epithelium (RPE) Cell Damages

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Abstract

Purpose:: The lipofuscin fluorophore A2E, a pyridinium bis-retinoid, is known to be an initiator of blue-light-induced apoptosis in retinal pigment epithelial cells (RPE). Degradation of A2E leads to the production of reactive oxygen species (ROS), which activate apoptosis and cell damage. The aim of this study is to gain insight into the mechanisms which underlie A2E-mediated damage to the RPE using bioorganic and biochemical studies.

Methods:: A2E and a bromo-derivative of A2E (A2E-Br), with a group carrying specific functionality for Mass-Spectrometry (MS) studies, were synthesized to provide a better tool for following A2E modification under blue light. A2E and its analog, A2E-Br, were loaded into RPE cell line for bio-analytical and biochemistry studies, including assessment of mitogen-activated protein kinase (MAPK) signal transduction changes by Western blot analysis.

Results:: A2E-like derivative under blue light irradiation was found to be suitable for bioanalytical research involving mass spectrometry studies. The bromine atom improved the detection of A2E MS fragments through the doublet Br isotope peaks. Blue light irradiation of A2E-Br results in the formation of reactive derivative that by MS/MS lead to aldehyde and dioxole fragments. We were able to show that A2E-Br cause similar toxic effects as the A2E to RPE cells following blue light exposure. MAPK pathway members were found to be activated following RPE loaded with A2E-Br and blue light irradiation.

Conclusions:: Investigating A2E-like compound modification under blue light and tracing some of the MAP-kinase intracellular changes enable us to obtain a better understanding of the factors mediating damage and/or taking part in cell rescue in retinal diseases and suggesting new target for A2E mediated damage prevention.
Original languageEnglish GB
Pages (from-to)2201
Number of pages1
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number13
StatePublished - 2007

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