Abstract
We have established that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, promotes survival of rat retina photoreceptors during early development in vitro and upon oxidative stress by activating the ERK/MAPK signaling pathway. Here we have investigated whether DHA turns on this pathway through activation of retinoid X receptors (RXRs) or by inducing tyrosine kinase (Trk) receptor activation. We also evaluated whether DHA release from phospholipids was required for its protective effect. Addition of RXR antagonists (HX531, PA452) to rat retinal neuronal cultures inhibited DHA protection during early development in vitro and upon oxidative stress induced with Paraquat or H2O2. In contrast, the Trk inhibitor K252a did not affect DHA prevention of photoreceptor apoptosis. These results imply that activation of RXRs was required for DHA protection whereas Trk receptors were not involved in this protection. Pretreatment with 4-bromoenol lactone, a phospholipase A2 inhibitor, blocked DHA prevention of oxidative stress-induced apoptosis of photoreceptors. It is noteworthy that RXR agonists (HX630, PA024) also rescued photoreceptors from H2O2-induced apoptosis. These results provide the first evidence that activation of RXRs prevents photoreceptor apoptosis and suggest that DHA is first released from phospholipids and then activates RXRs to promote the survival of photoreceptors.
Highlights
We have established that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, promotes survival of rat retina photoreceptors during early development in vitro and upon oxidative stress by activating the ERK/MAPK signaling pathway
retinoid X receptor (RXR) antagonists blocked DHA protective effects on photoreceptor degeneration in vitro We have established that DHA protects retina photoreceptors from apoptosis induced by oxidative stress or trophic factor deprivation
To investigate whether DHA exerted its protective effect through activation of RXRs, retinal neurons were either treated or not treated with the RXR pan-antagonists, HX531 or PA452, prior to the addition of bovine serum albumin (BSA) or DHA, and exposed to oxidative damage or cultured for 6 days without trophic factors (BSA control) or with DHA
Summary
We have established that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, promotes survival of rat retina photoreceptors during early development in vitro and upon oxidative stress by activating the ERK/MAPK signaling pathway. DHA promotes differentiation and postpones apoptosis of photoreceptors, which otherwise occurs in the absence of trophic factors during their early development in culture [2,3,4]; it effectively prevents photoreceptor apoptosis due to oxidative stress induced by Paraquat (PQ) [5] and H2O2 [6]. This antiapoptotic effect is highly specific for DHA, because other saturated, monoenoic, or polyunsaturated fatty acids cannot stop photoreceptor death [2].
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