CONICET | Buscador de Institutos y Recursos Humanos

In several retinal neurodegenerative diseases photoreceptors die through apoptosis. Our laboratory has previously reported that docosahexaenoic acid (DHA) is essential to protect photoreceptors from apoptosis induced by the oxidant paraquat (PQ). We have recently shown that ceramide is a mediator of photoreceptor apoptosis and that DHA prevents apoptosis by decreasing ceramide levels. We have investigated whether other sphingolipids regulate photoreceptor survival. Sphingosine (Sph), which is generated by ceramide hydrolysis, induces apoptosis in many cell types. We have previously shown that Sph addition to rat retina neuronal cultures induced photoreceptor apoptosis, while inhibiting Sph synthesis markedly reduced apoptosis induced by oxidative stress. To evaluate whether oxidative stress increased Sph synthesis, cultures were incubated with [3H]palmitate and then treated with PQ; this treatment increased [3H]Sph levels. These results suggest that Sph is, together with ceramide, a mediator of photoreceptor death upon oxidative stress. Sph can be phosphorylated and form sphingosine-1-phosphate (S1P), which has anti-apoptotic properties. Addition of S1P to retinal cultures before PQ or Sph treatment blocked photoreceptor apoptosis. We investigated whether DHA prevented Sph-induced apoptosis and if this protection involved S1P synthesis. DHA supplementation protected photoreceptors from Sph-induced apoptosis and, inhibiting Sph phosphorylation blocked DHA protective effect on Sph and PQ-induced apoptosis. We then incubated cultures supplemented or not with DHA with [3H]Sph; DHA-supplemented cultures showed higher levels of [3H]S1P than cultures lacking DHA. As a whole, these results suggest that oxidative stress induces ceramide and Sph synthesis in photoreceptors to trigger photoreceptor apoptosis. On the contrary, S1P acts as a key mediator of photoreceptor survival and DHA promotes its synthesis to prevent photoreceptor apoptosis.