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N. P. Rotstein, C. E. Abrahan, G. E. Miranda; Docosahexaenoic Acid Promotes Photoreceptor Survival and Differentiation by Regulating Sphingolipid Metabolism. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1349.
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Improving our knowledge of the molecular steps involved in photoreceptor death, and in its prevention by trophic factors is crucial for finding new strategies for treating retina degeneration. We have recently shown that the sphingolipid ceramide is a key mediator in oxidative stress-induced apoptosis of photoreceptors (German et al, IOVS 47: 1658, 2006). We also demonstrated that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, which promotes photoreceptor survival and differentiation, prevents apoptosis by lowering ceramide levels. Ceramide levels can decrease through its breakdown by ceramidases to sphingosine (Sph), an established proapototic sphingolipid, which, in turn, can be phosphorylated by sphingosine kinase (SK) to form sphingosine-1-phosphate (S1P), shown to have an antiapoptotic function. We now investigated whether DHA modulated these pathways to promote photoreceptor survival.
Pure rat retina neurons in culture, supplemented with or without DHA, were treated with Sph or S1P. Inhibitors of alkaline ceramidase or SK were also added to these cultures to block Sph and S1P synthesis, respectively, before treatment of the cultures with either C2-ceramide (Cer) or paraquat (PQ). Apoptosis, mitochondrial membrane polarization and opsin expression were then determined in photoreceptors.
Sph addition induced photoreceptor death, while pre-treatment with DHA or inhibition of Sph endogenous synthesis before Cer or PQ treatment prevented photoreceptor apoptosis, preserving mitochondrial membrane polarization. In contrast, S1P supplementation prevented Cer or PQ-induced apoptosis of photoreceptors, while inhibition of S1P synthesis before Cer or PQ treatment completely blocked DHA protection. In addition, inhibiting S1P synthesis prevented the increase in opsin expression induced by DHA in photoreceptors.
These results suggest that Sph is a mediator of oxidative stress-induced apoptosis. On the contrary, while an augmented synthesis of S1P prevents apoptosis and participates in DHA effects on survival and differentiation. DHA regulation of the balance between pro and antiapoptotic sphingolipids seems crucial for photoreceptor survival. Modulation of this balance might provide a therapeutic tool for rescuing photoreceptors in retina degeneration.
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