Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1

Department of Ophthalmology, School of Medicine, Louisiana State University Health Sciences Center, Neuroscience Center of Excellence, New Orleans, LA 70112, USA.
The Journal of Lipid Research (Impact Factor: 4.42). 04/2010; 51(8):2018-31. DOI: 10.1194/jlr.R001131
Source: PubMed


Retinal degenerative diseases result in retinal pigment epithelial (RPE) and photoreceptor cell loss. These cells are continuously exposed to the environment (light) and to potentially pro-oxidative conditions, as the retina's oxygen consumption is very high. There is also a high flux of docosahexaenoic acid (DHA), a PUFA that moves through the blood stream toward photoreceptors and between them and RPE cells. Photoreceptor outer segment shedding and phagocytosis intermittently renews photoreceptor membranes. DHA is converted through 15-lipoxygenase-1 into neuroprotectin D1 (NPD1), a potent mediator that evokes counteracting cell-protective, anti-inflammatory, pro-survival repair signaling, including the induction of anti-apoptotic proteins and inhibition of pro-apoptotic proteins. Thus, NPD1 triggers activation of signaling pathway/s that modulate/s pro-apoptotic signals, promoting cell survival. This review provides an overview of DHA in photoreceptors and describes the ability of RPE cells to synthesize NPD1 from DHA. It also describes the role of neurotrophins as agonists of NPD1 synthesis and how photoreceptor phagocytosis induces refractoriness to oxidative stress in RPE cells, with concomitant NPD1 synthesis.

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    • "The end-product is 10(S),17(S)-dihydroxy- 4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid[16]. This product has been named protectin DX (PDX) to differentiate it from protectin D1 (PD1), also called neuroprotectin D1 (NPD1) because of its occurrence in the brain where it exert neuroprotective activities[17]. PD1 (10(R),17(S)-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-docosahexaenoic acid) differs from PDX both by the stereochemistry of carbon 10 (R instead of S) and the conjugated triene geometry (E,E,Z instead of E,Z,E)[18]. Like all the other E,Z,E conjugated trienes (named poxytrins ® , Fig. 1) tested, including the other double lipoxygenation endproducts 8S,15S-diHETE from 20:4u6, 10(S),17(S)-dieOHe22:3 from 22:3u6 and 7(S),14(S)-dieOHe22:6, the latter being a geometric and stereo-isomer of maresin 1[19], PDX inhibits human blood platelet aggregation induced by both collagen and thromboxane . "
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    • "acute inflammatory responses) are programmed to be self-limited and tightly controlled [8] [9] [10]. Lipid mediators such as prostaglandins and leukotrienes play pivotal roles in the initiation of acute inflammation [11], whereas resolvins and protectins promote and stimulate active resolution [8] [9] [12]. In excess, prostaglandins and leukotrienes are generally pro-inflammatory [11] and involved in the classic initiation phase of the acute inflammatory response in humans. "
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    • "These data indicate tight regulation of DHA homeostasis in RPE cells. The DHA-derived compounds, protectin D1, neuroprotectin D1 and resolvin D1, have been identified as anti-inflammatory lipid mediators (Bazan et al., 2010; Mukherjee et al., 2004; Serhan et al., 2004). Therefore, the well-recognized role of CYP4 enzymes in fatty acid metabolism and the suspected abnormal lipid metabolism in BCD raises the possibility that a deficiency in the PUFAhydroxylase catalytic function of CYP4V2 might play a role in BCD (Kelly et al., 2011). "
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