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N.P. Rotstein, O.L. German, C.E. Abrahan, G.E. Miranda; Ceramide Is a Key Mediator in the Apoptosis of Retina Photoreceptors . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1674.
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Purpose: Oxidative stress has a critical role in triggering photoreceptor apoptosis. However, the precise molecular mechanisms that induce the death of these cells are still unclear. We had previously shown that oxidative stress, generated by the oxidant paraquat (PQ) induces apoptosis in retina photoreceptor neurons, while docosahexaenoic acid (DHA), retina major polyunsaturated fatty acid, prevents this apoptosis. In this work we investigated whether ceramide, a sphingolipid that activates apoptosis in response to cellular stress, participates in the induction of photoreceptor apoptosis upon oxidative stress. Methods: rat retina neuronal cultures, with or without DHA, were treated with the cell permeable ceramide analog, acetyl–sphingosine (C2–ceramide), or the oxidant paraquat (PQ); neuronal apoptosis, mitochondrial membrane integrity and Bcl–2 expression were evaluated after 24 hs. Results: C2–ceramide markedly increased apoptosis in photoreceptor and amacrine neurons, decreasing mitochondrial membrane integrity. Inhibition of sphingolipid synthesis with fumonisin B1 substantially reduced oxidative stress–induced photoreceptor apoptosis, preserving mitochondrial membrane integrity. This suggests that an increase in ceramide synthesis triggers photoreceptor apoptosis. DHA completely prevented C2–ceramide–induced photoreceptor death, increasing Bcl–2 expression in photoreceptors and precluding mitochondrial depolarization. Inhibition of glucosylceramide synthase, which catalyzes ceramide glucosylation, before C2–ceramide or PQ treatment, blocked DHA protective effect. Conclusions: these results suggest that oxidative stress increases ceramide synthesis, which in turn triggers photoreceptor apoptosis. DHA prevents apoptosis by enhancing Bcl–2 expression and simultaneously reducing ceramide endogenous levels by increasing ceramide glucosylation. In summary, this work shows for the first time that ceramide is a key mediator in the activation of photoreceptor apoptosis in mammalian retina. It also suggests that lowering ceramide levels by regulating the enzymes involved in sphingolipid metabolism might offer a therapeutic strategy to prevent photoreceptor death in neurodegenerative diseases.
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