Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration.

Many pathologies of the central nervous system (CNS) originate from excess of reactive free radicals, notably reactive oxygen species (ROS), and oxidative stress. A phenomenon which usually runs in parallel with oxidative stress is unsaturated lipid peroxidation, which, via a chain reaction, contributes to the progression of disbalanced redox homeostasis. Among long-chain (LC) polyunsaturated fatty acids (PUFAs) abundantly occurring in the CNS, docosahexaenoic acid (DHA), a member of ω-3 LC-PUFAs, deserves special attention, as it is avidly retained and uniquely concentrated in the nervous system, particularly in retinal photoreceptors and synaptic membranes; owing to the presence of the six double bonds between carbon atoms in its polyene chain (C=C), DHA is exquisitely sensitive to oxidative damage. In addition to oxidative stress and LC-PUFAs peroxidation, other stress-related mechanisms may also contribute to the development of various CNS malfunctions, and a good example of such mechanisms is the process of lipofuscin formation occurring particularly in the retina, an integral part of the CNS. The retinal lipofuscin is formed and accumulated by the retinal pigment epithelial (RPE) cells as a consequence of both visual process taking place in photoreceptor-RPE functional complex and metabolic insufficiency of RPE lysosomal compartment. Among various retinal lipofuscin constituents, bisretinoids, originating from all-trans retinal substrate--a photometabolite of visual pigment cofactor 11-cis-retinal (responsible for photon capturing), are endowed with cytotoxic and complement-activating potential which increases upon illumination and oxidation. This survey deals with oxidative stress, PUFAs (especially DHA) peroxidation products of carboxyalkylpyrrole type and bisretinoids as potential inducers of the CNS pathology. A focus is put on vision-threatening disease, i.e., age-related macular degeneration (AMD), as an example of the CNS disorder whose pathogenesis has strong background in both oxidative stress and lipid peroxidation products.