12.Belcaro G, Cesarone MR, Steigerwalt RJ, et al. Jet-lag: prevention with Pycnogenol. Preliminary report: evaluation in healthy individuals and in hypertensive patients. Minerva Cardioangiol 2008; 56(5 Suppl): 3-9.

13.Feng WY, Tanaka R, Inagaki Y, et al. Pycnogenol, a procyanidin-rich extract from French maritime pine, inhibits intracellular replication of HIV-1 as well as its binding to host cells. Jpn J Infect Dis 2008; 61: 279-285.

14.Dvoráková M, Jezová D, Blazícek P, et al. Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (pycnogenol). Nutr Neurosci 2007 ; 10: 151-157.

15.Grimm T, Chovanova Z, Muchova J, et al. Inhibition of NF-kappaB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol). J Inflamm (Lond) 2006; 27: 1.

16.Schafer A, Chovanova Z, Muchova J, et al. Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol). Biomed Pharmacother 2006; 60: 5-9.

17.Kobayashi MS, Han D, Packer L. Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res 2000; 32: 115-124.

18.Peng QL, Buz’Zard AR, Lau BH. Pycnogenol((R)) protects neurons from amyloid-beta peptide-induced apoptosis. Brain Res Mol Brain Res 2002; 104: 55-65.

19.Packer L, Rimbach G,Virgili F. Antioxidant activity and biologic properties of a procyanidinrich extract from pine (Pinus maritima) bark, pycnogenol. Free Radic Biol Med 1999; 27: 704-724.

20.Schonlau F, Rohdewald P. Pycnogenol for diabetic retinopathy. A review. Int Ophthalmol 2001; 24: 161-171.

21.Kamuren ZT, McPeek CG, Sanders RA, Watkins JB 3rd. Effects of low-carbohydrate diet and Pycnogenol treatment on retinal antioxidant enzymes in normal and diabetic rats. J Ocul Pharmacol Ther 2006; 22: 10-18.

22.Steigerwalt R, Belcaro G, Cesarone MR, et al. Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocul Pharmacol Ther 2009; 25: 537-540.

23.Steigerwalt RD, Gianni B, Paolo M, et al. Effects of Mirtogenol on ocular blood flow and intraocular hypertension in asymptomatic subjects. Mol Vis 2008; 14: 1288-1292.

Fish oil and omega-3 fatty acids

Sandra Fernando

Pharmacology

Omega-3 fatty acids, found most notably in fish oil, include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These are long-chain polyunsaturated fatty acids (PUFAs) with an 18-carbon chain precursor that cannot be synthesized by mammals. Therefore, these fatty acids must be obtained through diet or supplementation. Once omega-3 fatty acids are ingested, they undergo elongation and desaturation to form long-chain metabolites that can eventually become incorporated into cell membranes.1 DHA has many diverse functions at the cellular level including enzyme regulation, membrane fluidity, regulation of ion channels and signal transduction.2

202

Fish oil, omega-3 fatty acids, and glaucoma

Aqueous production involves membrane-bound pumps and receptors. Omega-3 deficiency can affect membrane-bound protein activity in rats3 and therefore may affect aqueous production. Increasing dietary omega-3 in mice reduces IOP by increasing outflow facility4 and diets with increased omega-3 and decreased omega-6 PUFA’s may favor increased synthesis of PG-F2.5 In rabbits, intramuscular cod liver oil lowered IOP by 3 mmHg at 0.2 ml/day, and 6.5 mmHg at 1 ml/day. When treatment with cod liver oil was stopped, IOP rose to baseline levels.6 However, human studies investigating dietary fat consumption and primary open-angle glaucoma (POAG) showed that a high ratio of dietary omega-3 to omega-6 polyunsaturated fat consumption appears to increase the risk of POAG.7 The trabecular meshwork in glaucoma is also affected by oxidative stress related changes such as cell loss, increased accumulation of extracellular matrix (ECM), and cellular senescence, which are minimized with prostaglandin analogue application in vivo.8

DHA and EPA play a role in red cell fluidity, deformability, and aggregability. 9 POAG patients are hypothesized to have enhanced platelet aggregation,10-12 and EPA is a precursor to eicosanoids, which have vasodilator and antiaggregatory effects.13,14 Reduced plasma EPA and DHA were found in glaucoma patients compared to siblings without glaucoma, and it was postulated that EPA and DHA play a role in modulating impaired systemic microcirculation and ocular blood flow in POAG.15

In the retina, DHA has been implicated in modifying enzyme activity in photoreceptor cells and providing an environment for conformational changes in rhodopsin. Decreased retinal DHA content affects visual function in monkeys16,17 and a combination of DHA, vitamin E, and vitamin B were reported to improve contrast sensitivity and visual field indices.18 In addition, DHA protects cells from oxidative stress by modulating levels of proand anti-apoptotic proteins of the Bcl-2 family, which protects photoreceptors from oxidative stress.19

DHA is also enriched in retinal pigment epithelial cells and is a precursor of neuroprotectin D1 (NPD1), which inhibits retinal pigment epithelial cell apoptosis and inhibits oxidative-stress-mediated pro-inflammatory gene induction.20 DHA also reduces the activation of kainate receptors in retinal reperfusion after ischemia, and is proposed to have a neuroprotective effect in ischemia-induced retinal injury. In rabbits, intraperitoneal DHA was effective in protecting the retina against IOP-induced transient ischemia.21 In addition, oral administration of DHA in rats counteracted kainic acid-induced retinal neurotoxicity22 and DHA protected against ischemia-reperfusion related retinal cell death in monkeys, partially by inhibiting the formation of hydroxyl radicals.23 In rodent eyes with laser photocoagulation-induced increased IOP, glial cell activation was significantly lower and protective effects on retinal structures was significantly higher in animals fed with an omega-3 and omega-6 PUFA combination diet compared to controls and those fed a single supplementation (omega-3 or

omega-6) diet.24 Lastly, DHA combined with lutein and zeaxanthin promotes rat photoreceptor survival after oxidative damage.25

Dosage and side effects

There are many types of nonprescription dietary supplements of omega-3 fatty acids available. However, none are regulated by the same standards as pharmaceutical agents.26 In 2004, the FDA approved a formulation of omega-3-acid ethyl esters to reduce high triglyceride levels, which is a combination of omega-3-acid ethyl esters (P-OM3). It contains concentrated forms of EPA (465 mg), DHA (375 mg) and other omega-3 fatty acids (60 mg) for a total of at least 900 mg of omega-3 fatty acids per each one-gram capsule.27 In patients with documented coronary heart disease, the American Heart Association recommends one gram of DHA and EPA for cardiovascular protection.28 The best dietary sources of EPA and DHA include fatty fish such as salmon, herring, mackerel, halibut and tuna29 and also some fresh-water fish such as lake herring, lake trout, freshwater salmon and whitefish.30(USDA)

The most common drug-related adverse events associated with omega 3 fatty acid supplementation include dyspepsia and belching.31 There are no known, clinically significant drug interactions; however, some reports suggest that omega-3 fatty acids may impair platelet aggregation and increase bleeding times.32,33 Omega-3 fatty acid supplementation has also been attributed to increased levels of liver transaminases,31 and a transient increase in glucose levels.27

In conclusion, omega-3 fatty acids play an important role in reducing oxidative damage in the retina, improving ocular blood flow and protecting against retinal ischemia induced by increased IOP.

References

1.Moyad MA. An introduction to dietary/supplemental omega-3 fatty acids for general health and prevention: part I. Urol Oncol 2005; 23: 28-35.

2.Chapkin RS, McMurray DN, Davidson LA, Fan YY, Lupton JR. Bioactive dietary long-chain fatty acids: emerging mechanisms of action. Br J Nutr 2008; 100: 1152-1157.

3.Gerbi A, Maixent JM, Barbey O, et al. Alterations of Na,K-ATPase isoenzymes in the rat diabetic neuropathy: protective effect of dietary supplemenation with n-3 fatty acids. J Neurochem 1998; 71: 732-740.

4.Nguyen CTO, Bui BV, Sinclair AJ, Vingrys AJ. Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing aqueous outflow facility. Invest Ophthalmol Vis Sci 2007; 48: 756-762.

5.Desmettre T, Rouland JF. Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma. J Fr Ophtalmol 2005; 28: 312-316.

6.Mancino M, Ohia E, Kulkarni P. A comparative study between cod liver oil and liquid lard intake on IOP in rabbits. Prostaglandins Leukot Essent Fatty Acids 1992; 45: 239-243.

7.Kang JH, Pasquale LR, Willett WC, et al. Dietary fat consumption and primary open-angle glaucoma. Am J Clin Nutr 2004; 79: 755-764.

204

8.Yu AL, Fuchshofer R, Kampik A, Welge-Lüssen U. Effects of oxidative stress in trabecular meshwork cells are reduced by prostaglandin analogues. Invest Ophthalmol Vis Sci 2008; 49: 4872-4880.

9.Popp-Snijders C, Schouten JA, van der Meer J, van der Veen EA. Fatty fish-induced changes in membrane lipid composition and viscosity of human erthrocyte suspensions. Scan J Clin La Invest 1986; 46: 253-258.

10.Bojic L, Mandic Z, Bukovic, D, et al. Circulating platelet aggregates and progression of visual field loss in glaucoma. Coll Antropol 2002; 26: 589-593.

11.Bojic L, Skare-Librenjak, L. Circulating platelet aggregates in glaucoma. Int Ophthalmol 1989; 22: 151-154.

12.Hoyng PF, de Jong N, Oosting H, Stilma J. Platelet aggregation, disc haemorrhage and progressive loss of visual fields in glaucoma, A seven year follow up study on glaucoma. Int Ophthalmol 1992; 16: 65-73.

13.Von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function and eicosanoid formation in humans. J Clin Invest 1985; 6: 1626-1631.

14.Calder PC. N-3 polyunsaturated fatty acids and inflammation: From molecular biology to the clinic. Lipids 2003; 38: 343-352.

15.Ren H, Magulike N, Ghebremeskel K, Crawford M. Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids. Prostaglandins, Leukotrienes and Essential Fatty Acids 2006; 74: 157-163.

16.Lin DS, Anderson GJ, Connor W, Neuringer M. Effect of dietary n-3 fatty acids upon the phospholipids molecular species of the monkey retina. Invest Ophthalmol Vis Sci 1994; 35: 794-803.

17.Ritch R. Natural compounds: evidence for a protective role in eye disease. Can J Ophthalmol 2007; 42: 425-438.

18.Cellini M, Caramazza N, Mangiafico P, Possati GL, Caramazza R. Fatty acid use in glaucomatous optic neuropathy treatment. Acta Ophthalmol Scand 1998; 227: 41-42.

19.Rotstein NP, Politi LE, German OL, Girotti R. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors. Invest Ophthalmol Vis Sci 2003; 44: 2252-2259.

20.Bazan NG. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 2006; 29: 263-271.

21.Miyauchi O, Mizota A, Adachi-Usami E. Protective effect of docosahexaenoic acid against retinal ischemic injury: an electroretinographic study. Ophthalmic Res 2001; 33:191-195.

22.Mizota A, Sato E, Taniai M, Adachi-Usami E, Nishikawa M. Protective effects of dietary docosahexaenoic acid against kainite induced retinal degeneration in rats. Invest Ophthalmol Vis Sci 2001; 42: 216-221.

23.Murayama K, Yoneya S, Miyauchi O, Adachi-Usami E, Nishikawa M. Fish oil (polyunsaturated fatty acid) prevents ischemic induced injury in the mammalian retina. Exp Eye Res 2002; 74: 671-676.

24.Schnebelen C, Pasquis B, Salinas-Navarro M, et al. A dietary combination of omega-3 and omega-6 polyunsaturated fatty acids is more efficient than single supplementations in the prevention of retinal damage induced by elevation of intraocular pressure in rats. Graefes Arch Clin Exp Ophthalmol 2009; 7: 1191-1203.

25.Chucair AJ, Rotstein MP, Sangiovanni JP, During A, Chew EY, Politi LE. Lutein and zeaxanthin protect photoreceptors from apaptosis induced by oxidative stress: relation with ocosahexenoid acid, Invest Ophthalmol Vis Sci 2007; 48: 5168-5177.

26.Bruntona S, Collins N. Differentiating prescription omega-3-acid ethyl esters (P-OM3) from dietary-supplement omega-3 fatty acids. Current Medical Research Opinion 2007; 23:11391145.

27.Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther 2008; 6: 391-409.