Grant Watters Title: Astaxanthin – a Potential Ocular Antioxidant?

OTC 2020 Presenter: Grant Watters Title: Astaxanthin – a potential ocular antioxidant?

Nutraceuticals and supplements

• To address dietary deficiencies (eg calcium, iron, magnesium, zinc) • For dietary top‐up/insurance policy • Improve cognition (reduce depression) • Slow down ageing Astaxanthin‐ a possible ocular • Health‐conscious (& exercise) • Adjunctive to improve bioavailabilty antioxidant? • Pet food (eg Radical Dog Biscuits!!) • USA useage: Grant Watters MScOptom, DipCLP 76% in 2018 (vs 64% in 2008) Very profitable multi‐billion dollar industry; unregulated & under‐researched in many areas

Different groups

• Vitamins & minerals • Herbs/spices/plant & berry extracts, amino acids, enzymes

FDA: “common ones” • Calcium *should not make disease claims • Echinacea (eg“lowers cholesterol”) • Fish Oil • Warns about overdosing, combining & substituting for • Ginseng Rx medicines • Glucosamine and/or Chondroitin Sulphate “oxidative tissue damage” • Garlic = ageing & disease • Vitamin D • St. John’s Wort “as we age, prooxidants overwhelm the eye’s • Saw Palmetto antioxidant defences resulting in oxidative • Ginkgo stress & damage to tissues associated with the development of ocular pathologies such as • Green Tea corneal opacities, cataracts & glaucoma” (Umapathy A, Donaldson P & Lim J, 2013)

General eye health nutrition Astaxanthin (ATX)

• D Astaxanthin‐ C40H52O4; 596.84 g/mol; red • Common marine powder; soluble in water and fat xanthrophyll carotenoid (main source marine algae H. pluvialis) • Closely related to human retinal pigments lutein & Zeaxanthin‐ C40H56O2; 568.88 g/mol; red‐ zeaxanthin orange; insoluble in water • Strongest antioxidant (AO) activity of all the carotenoids • Lipid soluble‐ so good Did Popeye escape AMD ? absorption across cell membranes Lutein‐ C40H56O2; 568.871 g/mol; red‐orange crystalline solid; insoluble in water; soluble in fat • Can cross blood‐retina and blood‐brain barrier (Tso, 1996)

Haematococcos pluvialis Existing researched benefits (humans)

• Freshwater green marine algae, can be • Ambati RR, Phang SM, Aswathanarayana RG. Astaxanthin: sources, extraction,stability, biological activities and its commercial applications‐ a review. Mar.Drugs 2014; 12: 128‐152. • de Jesus Raposo MF, de Morais AMMB, de Morais RMSC. Carotenoids from marine microalgae: a farmed valuable natural source for the prevention of chronic diseases. Mar.Drugs 2015; 13: 5128‐5155. • Exercise recovery • Zhang L, Wang H. Multiple mechanisms of anti‐cancer effects exerted by astaxanthin. Mar.Drugs 2015; • Encysts & produces ATX as a protector 13: 4310‐4330. • Reduced joint • El‐Baky HH, El‐Baroty GS. The potential use of microalgal carotenoids as dietary supplements and natural against stress conditions such as UV preservative ingredients. J.Aq. Food Prod.Tech 2013; 22: 39‐406. • Biswal S. Oxidative stress and astaxanthin: the novel supernutrient carotenoid. Int. J Health. All. Sci 2014; inflammation 3(3): 147‐153. light, high salinity, low nutrient • Li S, Chen G, Zhang C, Wu M, Wu S, Liu Q. Research progress of natural antioxidants in foods for the treatment of diseases. Food. Sci.Human.Well 2014; 3: 110‐116. availability & high temperature • Improved mitochondrial • Birch‐Machin MA, Bowman A. Oxidative stress and ageing. B.J. Derm2016; 175: 26‐29. • Guerin M, Huntley ME, Olaizola M. Haematococcus astaxanthin: applications for human health and • High bioavailability from dual lipophilic function nutrition. Trend.Biotech 2003; 21(5): 210‐216. A coccal H. pluvialis cell, • Park JS, Chyun JH, Kim YK, Line LL, Chew BP. Astaxantin decreased oxidative stress and inflammation and enhanced immune response in humans. Nut & Met2010; 7(18): 1‐10. and hydrophilic properties across CMs void of astaxanthin • Skin protection (UV) • Kohler A, Sarkkinen E, Tapola N, Niskanen T, Bruheim I. Bioavailability of fatty acids from krill oil, krill meal and fish oil in healthy subjects‐ a randomised, single‐dose, cross‐over trial. Lip. Health.Dis 2015; • AO activity of ATX: 14(19): 1‐10. • Anti‐diabetic • Curek GD, Cort A, Yucel G, Demir N, Ozturk S, Elpeck G, Savas B, Aslan M. Effect of astaxanthin on hepatocellular injury following ischaemia/reperfusion. Toxicology 2010; 267: 147‐153. 10 x zeaxanthin, lutein & B‐carotine • Kim YJ, Kim YA, Yokozawa T. Protection against oxidative stress, imflammation, and apoptosis of high • Immunomodulation glucose‐exposed proximal tubular epithelial cells by astaxanthin. J.Ag.Food Chem2016; online doi: 10.1021/jf9019745. 500 x Vit A • Naito Y, et al. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. • Neuro‐protection Biofactors 2004; 20(1): 49‐59. • Hussein G et al. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. 65 x Vit C Bio.Phar.Bulletin 2005; 28(1): 47‐52. • Cardiovascular disease • Katagiri M, Satoh A, Tsuji S, Shirasawa T. Effects of astaxanthin‐rich Haematococcus pluvialis extract on cognitive function: a randomised, double‐blind placebo‐controlled study. J.Clin.Biochem.Nutr. 2012; Also has immunomodulation & anti‐ 51(2): 102‐107. • Anti‐cancer • Tso MOM, Lam T‐T. Method of retarding and ameliorating central nervous system and eye damage. U.S. inflammatoy properties‐ reduces C‐Rp, Patent #5527533 1996 H. pluvialis cysts full of • Yoshihisa Y et al. Efficacy of astaxanthin for the treatment of atopic dermatitis in a murine model. Plos boosts NK, T & B‐ cells, cytokines one 2016; online doi: 10.1371/015288. astaxanthin • Savoure N et al. Vitamin A status and metabolism of cutaneous polyamines in the hairless mouse after UV irradiation: action of beta‐carotine and astaxanthin. Int.J.Vitam.Nutr.Res 1995; 65: 79‐86.

ATX and the eye‐ existing study data and Existing products potential investigations?

• McCusker MM, Durrani K, Payette MJ, Suchecki J. An eye on nutrition: the role of vitamins, essential fatty acids, and • Dry eye disease: krill oil‐ antioxidants in age‐related macular degeneration, dry eye syndrome, and cataract. Clin.Dermat 2016; 34: 276‐285. phospholipid containing AXT > • Wakamatsu TH, Dogru M, Tsubota K. Tearful relations: oxidative stress, inflammation and eye diseases. Arq. Bras. fish oil‐ less inflammatory Oftalmol 2008; 71(6): 72‐79. • Yamada T et al. Evaluation of therapeutic effects of markers astaxanthin on impairments in salivary secretion. J.Clin.Biochem.Nutr 2010; 47: 130‐137. • Uchino Y et al. Oxidative stress induced inflammation initiates functional decline of tear production. Plos one 2012; 7(10): e45805. • : helps salivary gland • Sheppard JD et al. Lifitegrast ophthalmic solution 5.0% Sjogrens? treatment of dry eye disease:results of the OPUS‐1 phase 3 study. Ophthalmol 2014; 121(2): 475‐483. (but no studies on lacrimal gland) • Deinema L et al. A randomised, double‐masked, placebo‐ controlled clinical trial of two forms of Omega‐3 supplements for treating dry eye disease. Ophthalmolol 2016; doi 10.1016/j.ophtha.2016.09.03 • Umapathy A, Donaldson P, Lim J. Antioxidant delivery • Aqueous humour: has pathways in the anterior eye. Biomed. Res. Int 2013; doi 10.1155/2013/207250. increased superoxide scavenging • Sacca SC, Izzotti A. Oxidative stress and glaucoma: injury in the anterior segment of the eye. Prog.Brain.Res 2008; 173: activity so potential less TM 385‐407. • Aslan M, Cort A, Yucel I. Oxidative and nitrative stress degeneration markers in glaucoma. Free Rad.Bio.Med 2008; 45: 367‐376. • Hashimoto H et al. Effects of astaxanthin on antioxidation in human aqueous humor. J.Clin.Biochem.Nutr 2013; 53(1): 1‐7.

ATX and the eye (con’d) ATX and the eye (con’d)

• Chrysostomou V, Rezania F, Trounce IA, Crowson JG. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr.Opin. Phar 2013; 13: 12‐15. • Piermarocchi S et al. Carotenoids in age‐related maculopathy Italian study (CARMIS): two‐year results of a randomised study. Eur.J.Ophthalmol 2012; 22(2): 216‐225. • Retina: AMD, DR and • Santocono M, Zurria M, Berrettini M, Fedeli D, Falcioni G. Influence of astazanthin, zeaxantin and lutein on DNA damage and repair in UVA‐irradiated • Crystalline lens: improved • Varma SD, Hegde KR. Oxidative stress and cells. J.Photochem.Photobiol.B 2006; 85(3): 205‐215. • Yeh P‐T, Huang H‐W, Yang C‐M, Yang W‐S, Yang C‐H. Astaxanthin inhibits cataract formation: horizons on its medical expression of retinal oxidative stress and inflammatory mediators in accommodation but no prevention. Future drugs 2007; doi glaucoma ? streptozotocin‐induced diabetic rats. Plos one 2016; doi: 10.1371/journal/pone.0146438. 10.1586/17469899.2.5.779. • Cort A et al. Suppressive effect of astaxanthin on retinal injury induced by cataract data (high dietary • RPE /photoreceptor damage/ageing elevated intraocular pressure. Reg.Tox.Phar 2010; 58: 121‐130. • Uchino Y, Uchino M, Dogru M, Fukagawa K, • Nakajima et al. Astaxanthin, a dietary carotenoid, protects retinal cells against Tsubota K. Improvement of accommodation oxidative stress in‐vitro and in mice in‐vivo. J. Phar.Pharmacol 2008; 60: 1365‐ intake of carotenoids – 1374. with anti‐oxidant supplementation in visual • Taskintuna I, Abdalla Elsayed MEA, Schatz P. Update on clinical trials in dry age‐ display terminal users. J.Nut.Health.Age related macular degeneration. Mid.East.Afr.J.Ophthalmol 2016; 23(1): 13‐26. lutein & zeaxanthin‐ is MURINE STUDIES: induced elevated • Schleicher M, Weikel K, Garber C, Taylor A. Diminishing risk for age‐related 2012; 16(5): 478‐481. macular degeneration with nutrition: a current view. Nutrients 2013; 5: 2405‐ IOPs, diabetic retinopathy, photostress 2456. assoc. with reduced risk of • Shiratori K, Ogami K, Nitta T. The effects of • Yong JJ, Scott IU, Greenberg PB. Ocular nutritional supplements: are their astaxanthin on accommodation and ingredients and manufacturers’ claims evidence‐based? Ophthamol 2015; 122: 595‐599. nuclear cataracts) asthenopia‐efficacy identification study in • Chew EY et al. Long term effects of vitamins C, E, Beta‐carotine and zinc on age‐ healthy volunteers. Clin. Med 2005; 21(6): related macular degeneration: AREDS report # 35. Ophthalmol 2013; 120(8): % of population‐ people aged 90 or over: 1604‐1611. 637‐650. • Chew EY et al. Lutein plus zeaxanthin and omega‐3 fatty acids for age‐related • Nagaki Y et al. Effects of astaxanthin on macular degeneration. The Age‐Related Eye Disease Study 2 (AREDS2) 1980‐ 2.8% randomised clinical trial. J.A.M.A.Ophthalmol 2013; 309(19): 2005‐2015. accommodation, critical flicker fusion and • Chew EY et al. Lutein/Zeaxanthin for the treatment of age‐related cataract: pattern visual evoked potential in visual AREDS2 randomised trial report # 4. J.A.M.A Ophthalmol 2013; 131 (7): 843‐850. 2020‐ 4.7% • Otsuka T et al. The protective effects of a dietary carotenoid, astaxanthin, display terminal users. J.Trad.Med 2002; against light‐induced retinal damage. J. Pharmacol.Sci 2013; 123(3): 209‐218. • Santocono M, Zurria M, Berrettini M, Fedeli D, Falconi G. Lutein, zeaxanthin and 19(5): 170‐173 astaxanthin protect against DNA damage in SK‐N‐SH human neuroblastoma 2050‐ 10% est. cells induced by reactive nitrogen species. J. Photochem.Photobiol.B 2007; 88: 1‐10. • Bernstein PS et al. The value of measurement of macular carotenoid pigment optical densities and distributions in age‐related macular degeneration and other retinal disorders. Vis.Res 2010; 50: 716‐728. •

So do we need another carotenoid? Other interesting compounds

• Saffron, tumeric & • The AREDS2 formula works chamomile best if poorer diet; risk of • Blueberry & goji berry advanced AMD was lowered by • All potent about 20% antioxidants and anti‐ • Could the AREDS2 formula be inflammatories; due for a review? similar list of alleged • Can non‐invasively measure benefits to ATX the macular carotenoid • Plenty of PubMed pigment optical density published studies on (MPOD) retinal protection

Crystal ball gazing…

• I think that over the next 5‐10 years there is going to be a surge of research attempting to legitimise some of these promising natural products • We have to persuade some of these producers to fund proper research‐ even 1 Masters/PhD is great “value for money”…