48 - Lipid Radicals Cause Light Induced-Retinal Degeneration

Abstract

Age-related macular degeneration (AMD) is a progressive degenerative disease of the macula, the centre of the retina. It is the most common cause of adult vision loss in developed countries, and the numbers of patients are increasing every year. Although the cause of AMD remains unknown, it is believed that chronic oxidative stresses, such as light, smoking, and radiation, are related to the progression of AMD, especially dry-type AMD. The retina consumes large amounts of oxygen per tissue, and has high oxygen tension. This leads to the production of excessive reactive oxygen species (ROS). In addition, polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid and arachidonic acid, are abundantly present in the retina. Thus, in the retina, ROS can easily oxidize PUFAs and produce lipid radicals, which are key factors in the chain reaction during lipid peroxidation (LPO). The resulting lipid radicals produce many kinds of reactive aldehydes, including 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These reactive aldehydes bind to intracellular proteins and DNA, and induce inflammation and apoptosis. In fact, LPO end-products often accumulate in the retina of elderly people and AMD animal models. However, there are hundreds of LPO end-products with different functions, and it is challenging to detect and inhibit all of these products in vivo . Here, we focused on lipid-derived radicals as common compounds in the production of reactive aldehydes and most upstream compounds during the LPO chain reaction. As lipid radicals are too highly reactive for detection in cells and animals, we recently developed a lipid radical detection fluorescent probe, NBD-Pen ( Nat Chem Biol , 2016). In this report, we describe imaging of lipid radicals in the retina using light-induced retinal damage models as dry-type AMD animal models, and the effect of a newly-synthesized lipid radical inhibition molecule, CPC-Pen, on AMD with therapeutic relevance.