PHARMACOLOGICAL MANIPULATION OF DOCOSAHEXAENOIC-PHOSPHOLIPID BIOSYNTHESIS IN PHOTORECEPTOR CELLS - IMPLICATIONS IN RETINAL DEGENERATION

Docosahexaenoic acid (22:6n-3, DHA) is derived in vertebrate animals from n-3 fatty acids present in the diet (i.e., alpha-linolenic acid, 18:3n-3 and/or other n-3-long chain polyunsaturated fatty acids) and is found in very high concentrations in phospholipids from membranes of the central nervous system. Disk membranes of photoreceptor outer segments and synaptic terminals display a preferential enrichment in DHA-phospholipids that appears to be necessary for normal excitable membrane functions. Because of the relevance of adequate DHA-phospholipid synthesis and sorting toward new assembled disk membranes and synaptic terminals, as well as the pathophysiological implications of abnormal DHA metabolism (including its synthesis, delivery to the retina, and incorporation into lipids by de novo and turnover pathways), we reviewed recent studies of: a) the preferential uptake and retention of DHA by photoreceptors and its metabolism as it is activated to DHA-CoA and incorporated preferentially into phospholipids; b) pharmacological manipulations using amphiphilic cationic drugs (i.e., propranolol) to show an active esterification of DHA into lipids via de novo synthesis; and c) perturbations in DHA metabolism in retinas from dogs with progressive rod-cone degeneration (prcd).