protectin-d1 and Retinal-Degeneration

Docosahexaenoic acid (DHA), the main omega-3 fatty acid, is concentrated and avidly retained in membrane phospholipids of the nervous system. DHA is involved in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. Neuroprotectin D1 (NPD1), the first-identified stereoselective bioactive product of DHA, exerts neuroprotection in models of experimental stroke by down-regulating brain ischemia reperfusion (BIR)-induced leukocyte infiltration, proinflammatory signaling, and infarct size. Moreover, NPD1 inhibits cytokine-mediated cyclooxygenase-2 (COX-2) expression. Photoreceptor membranes display the highest content of DHA of any cell. Retinal pigment epithelial cells participate in the phagocytosis of the tips of photoreceptor cells (photoreceptor outer segment renewal). There is a DHA retrieval-intercellular mechanism between both types of cells that conserves this fatty acid during this process. NPD1 promotes homeostatic regulation of the integrity of these two cells, particularly during oxidative stress, and this protective signaling may be relevant in retinal degenerative diseases. Moreover, neurotrophins are NPD1-synthesis agonists, and NPD1 content is decreased in the CA1 region of the hippocampus of Alzheimer's patients. Overall, NPD1 promotes brain cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Abeta42 production and its neurotoxicity. Thus, NPD1 elicits potent cell-protective, anti-inflammatory, prosurvival repair signaling.

Topics: Alzheimer Disease; Animals; Cell Survival; Docosahexaenoic Acids; Humans; Retinal Degeneration; Signal Transduction; Stroke

Recent data have provided important clues about the molecular mechanisms underlying certain retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration. Photoreceptor cell degeneration is a feature common to these diseases, and the death of these cells in many instances seems to involve the closely associated retinal pigment epithelial (RPE) cells. Under normal circumstances, both cell types are subject to potentially damaging stimuli (e.g. sunlight and high oxygen tension). However, the mechanism or mechanisms by which homeostasis is maintained in this part of the eye, which is crucial for sight, are an unsolved riddle. The omega-3 fatty acid family member docosahexaenoic acid (DHA), which is enriched in these cells, is the precursor of neuroprotectin D1 (NPD1). NPD1 inhibits oxidative-stress-mediated proinflammatory gene induction and apoptosis, and consequently promotes RPE cell survival. This enhanced understanding of the molecular basis of endogenous anti-inflammatory and neuroprotective signaling in the RPE presents an opportunity for the development of therapies for retinal degenerative diseases.

Topics: Animals; Cell Death; Cell Survival; Docosahexaenoic Acids; Humans; Nerve Degeneration; Oxidative Stress; Photoreceptor Cells; Pigment Epithelium of Eye; Retinal Degeneration; Signal Transduction

Dysregulated neuroinflammatory signaling during impending disruption of homeostasis in retinal pigment epithelium (RPE) and photoreceptor cells (PRC) takes place in early stages of retinal degeneration. PRCs avidly retain and display the highest content in the human body of docosahexaenoic acid (DHA; an omega-3 essential fatty acid). Docosanoids are DHA-derived mediators, such as neuroprotectin D1 (NPD1), made on-demand that promote repair, phagocytic clearance, cell survival, and are active participants of effective, well-concerted homeostasis restoration. Here we develop the concept that there is a molecular logic that sustains PRC survival and that transcriptional signatures governed by NPD1 in the RPE may be engaged.

Topics: Cell Survival; Docosahexaenoic Acids; Eicosanoids; Homeostasis; Humans; Models, Biological; Phospholipids; Photoreceptor Cells, Vertebrate; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction

The significance of the selective enrichment in omega-3 essential fatty acids (docosahexaenoyl - DHA - chains of membrane phospholipids, 22C and 6 double bonds) in the nervous system (e.g. synaptic membranes and dendrites) has remained, until recently, incompletely understood. While studying mechanisms of neuronal survival, we contributed to the discovery of a docosanoid synthesized by 15-lipoxygenase-1 from DHA, which we dubbed neuroprotectin D1 (NPD1;10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). NPD1 is a docosanoid because it is derived from a 22C precursor (DHA), unlike eicosanoids, which are derived from the 20C arachidonic acid family of essential fatty acids not enriched in the nervous system. We found that NPD1 is promptly made in response to oxidative stress, seizures and brain ischemia-reperfusion. NPD1 is neuroprotective in experimental brain damage, retinal pigment epithelial cells, and in human brain cells. Thus, NPD1 acts as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by neurodegenerations. NPD1 also has been shown to have a specificity and potency that provides beneficial bioactivity during initiation and early progression of neuronal and retinal degenerations, epilepsy and stroke. In short, NPD1 regulation promotes homeostatic regulation of neural circuitry integrity.

Topics: Animals; Brain; Brain Diseases; Brain Ischemia; Docosahexaenoic Acids; Epilepsy; Humans; Oxidative Stress; Retina; Retinal Degeneration; Stroke

Retinal pigment epithelial (RPE) cells are the most restrictive layer of the three components of the outer Blood-Retina Barrier, preventing the passage of biomolecules in relation to size and charge and thus preserving a controlled environment for the photoreceptors. The retinal pigment epithelium is a tight structure that, when disrupted as a cause or consequence of pathological conditions, deeply affects the neural retina. Since adult human RPE cells are not replicative cells, their preservation is of major interest for the biomedical field due to their loss in many retino-degenerative pathologies. There are several triggers that elicit reactive oxygen species (ROS) formation in normal and pathological circumstances. When the production of these species overwhelms the scavenging and detoxifying systems, their activity results in programmed cell death. Docosahexaenoic acid (DHA) is an essential lipid that is conspicuously accumulated in photoreceptors and RPE cells in the retina. DHA and its oxygenation product, neuroprotectin D1 (NPD1), are major players in the protection of these cells and the retina. NPD1 promotes the synthesis of anti-apoptotic proteins of certain members of the Bcl-2 family and blocks the expression of pro-inflammatory proteins like cyclooxygenase-2.

Topics: Apoptosis; Cell Death; Cell Survival; Cytoprotection; Docosahexaenoic Acids; Humans; Inflammation; Oxidative Stress; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction

Photoreceptor survival depends on the integrity of retinal pigment epithelial (RPE) cells. The pathophysiology of several retinal degenerations involves oxidative stress-mediated injury and RPE cell death; in some instances it has been shown that this event is mediated by A2E and its epoxides. Photoreceptor outer segments display the highest DHA content of any cell type. RPE cells are active in DHA uptake, conservation, and delivery. Delivery of DHA to photoreceptor inner segments is mediated by the interphotoreceptor matrix. DHA is necessary for photoreceptor function and at the same time is a target of oxidative stress-mediated lipid peroxidation. It has not been clear whether specific mediators generated from DHA contribute to its biological properties. Using ARPE-19 cells, we demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin Dl (NPDI)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1 3P, or by supplying DHA. Added NPD1 (50nM) potently counteracted H2O2/tumor necrosis factor-alpha oxidative stress-triggered apoptotic DNA damage in RPE. NPD1 also up-regulated the anti-apoptotic proteins Bcl-2 and Bcl-xL and decreased pro-apoptotic Bax and Bad expression. Moreover, NPD1 (50nM) inhibited oxidative stress-induced caspase-3 activation. NPD1 also inhibited IL-1beta-stimulated expression of COX-2. Furthermore, A2E-triggered oxidative stress induction of RPE cell apoptosis was also attenuated by NPD1. Overall, NPD1 protected RPE cells from oxidative stress-induced apoptosis. In conclusion, we have demonstrated an additional function of the RPE: its capacity to synthesize NPD1. This new survival signaling is potentially of interest in the understanding of the pathophysiology of retinal degenerations and in exploration of new therapeutic modalities.

Topics: Animals; Apoptosis; Cell Line; Docosahexaenoic Acids; Light; Models, Chemical; Oxidative Stress; Oxygen; Phospholipases A; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Pigment Epithelium of Eye; Retina; Retinal Degeneration; Signal Transduction