Docosahexaenoic acid promotes photoreceptor survival upon oxidative stress by controlling sphingolipid metabolism

ROTSTEIN NP; MIRANDA GE; ABRAHAN CE; GERMAN OL

Fort Myers, Florida, EEUU

Conferencia; Summer Eye Research Conference, ARVO; 2006

ARVO

Docosahexaenoic Acid Protects Photoreceptors from Oxidative Stress by Controlling Sphingolipid Metabolism Rotstein N., Miranda G. , Abrahan C., German L. Instituto de Investigaciones Bioquímicas, UNS-CONICET, Bahía Blanca, Buenos Aires, Argentina.   Purpose: Apoptosis leads to photoreceptor death in many retina degenerative diseases; hence, establishing the pathways that prevent this death is essential to develop therapeutical strategies for treating these diseases. We recently showed that an increase in the intracellular level of the sphingolipid ceramide triggers photoreceptor death after oxidative stress. Ceramide level can decrease through its glucosylation to glucosylceramide or through its metabolization to sphingosine, which is in turn phosphorylated by sphingosine kinase (SK) to sphingosine-1-phosphate (S1P), a sphingolipid with antiapoptotic effects in several cell systems. We have now investigated whether docosahexaenoic acid (DHA), which protects photoreceptors from oxidative stress, might regulate sphingolipid metabolism to achieve this protection. Methods: Rat retina neuronal cultures, with or without DHA, were treated with C2-ceramide (Cer) or with either a glucosylceramide synthase (GCS) inhibitor, or a SK inhibitor prior to their treatment with Cer or the oxidant paraquat (PQ). Apoptosis, mitochondrial functionality and opsin expression were then determined. Results: DHA protected photoreceptors from apoptosis induced by Cer. The GCS inhibitor blocked DHA protective effect, increasing photoreceptor apoptosis induced by both Cer and PQ in DHA-treated cultures. When the SK inhibitor was added to DHA-treated cultures, it also blocked DHA protection from apoptosis induced by Cer and PQ. In addition, early inhibition of S1P synthesis in DHA-treated cultures reduced opsin expression in photoreceptors, suggesting that DHA might enhance S1P synthesis to promote both survival and differentiation. Conclusions: Cell survival has been proposed to depend on the balance between ceramide and S1P intracellular levels. DHA might prevent photoreceptor death by controlling this balance, decreasing ceramide level through its glucosylation to glucosylceramide and through its simultaneous conversion to S1P, with its resulting antiapoptotic effect. These results suggest that regulation by DHA of the enzymes of sphingolipid metabolism is crucial to prevent photoreceptor apoptosis upon oxidative stress.