Diabetic Retinopathy - Treatment

Omega-3 - updated: 15 March 2008

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Nat Med. 2007 Jul;13(7):868-73. Epub 2007 Jun 24

Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem N Jr, Serhan CN, Smith LE.

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of omega-3- and omega-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing omega-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive omega-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of omega-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-alpha. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of omega-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in omega-3-PUFA, and premature infants lack the important transfer from the mother to the infant of omega-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing omega-3-PUFA intake may be of benefit in preventing retinopathy.

Anti-inflammatory effect of docosahexaenoic acid on cytokine-induced adhesion molecule expression in human retinal vascular endothelial cells

Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4342-7.

Chen W, Esselman WJ, Jump DB, Busik JV.

PURPOSE: Docosahexaenoic acid (DHA(22:6n3)), the principal n3-polyunsaturated fatty acid (PUFA) in the retina, has been shown to have a pronounced anti-inflammatory effect in numerous in vivo and in vitro studies. Despite the importance of vascular inflammation in diabetic retinopathy, the anti-inflammatory role of DHA(22:6n3) in cytokine-stimulated human retinal vascular endothelial cells (hRVECs) has not been addressed. METHODS: Cytokine-induced expression of cell adhesion molecules (CAMs) was assessed by Western blot. The effect of DHA(22:6n3) on cytokine-induced nuclear factor (NF)-kappaB signaling was analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA). RESULTS: Stimulation of hRVECs with VEGF(165), TNFalpha, or IL-1beta for 6 to 24 hours caused significant induction of intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression. Pretreatment of the cells with 100 microM of BSA-bound DHA(22:6n3) for 24 hours remarkably inhibited cytokine-induced CAM expression. IL-1beta, TNFalpha, and VEGF(165) induced nuclear translocation and binding of p65 and p50 NF-kappaB isoforms to the VCAM-1 promoter. DHA(22:6n3) pretreatment inhibited cytokine-induced NF-kappaB binding by 25% to 40%. Moreover, DHA(22:6n3) diminished IL-1beta induced phosphorylation of the inhibitor of nuclear factor (NF)-kappaB (I-kappaBalpha), thus preventing its degradation. CONCLUSIONS: IL-1beta, TNFalpha, and VEGF(165) induced CAM expression in hRVECs through activation of the NF-kappaB pathway. DHA(22:6n3) inhibited cytokine induced CAM expression through suppression of NF-kappaB nuclear translocation and upstream I-kappaBalpha phosphorylation and degradation. DHA(22:6n3) could be an important anti-inflammatory agent in the face of increased cytokine production and CAM expression in the diabetic retina.

Effects of Omega-3 Fatty Acids on Eye Health

AHRQ Evidence Reports, Numbers 61 - 119

William Hodge MD David Barnes MD Howard M Schachter PhD Yi Pan MSc Elizabeth C Lowcock BScH Li Zhang MLIS Margaret Sampson MLIS Andra Morrison BSc Khai Tran PhD Maia Miguelez PhD Gabriela Lewin MD

This report is based on research conducted by the University of Ottawa Evidence-based Practice Center (EPC), under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0021). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers, patients and clinicians, health system leaders, and policymakers make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report as they would any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. Neither AHRQ's nor the U.S. Department of Health and Human Services' endorsement of such derivative products may be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Publication Types:

• Review

The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina

Prog Retin Eye Res. 2005 Jan;24(1):87-138

SanGiovanni JP, Chew EY.

In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.

Publication Types:

• Review

Publication Types:

• Review