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[23/04/2014] Resveratrol for ocular diseases

 Reseveratrol has shown beneficial effects in degenerative eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DRP) and age-related cataracts

 

 Age-related macular degeneration (AMD):

AMD is a leading cause of adult vision loss in developed countries. According to one estimate 17,100 new cases of neovascular (wet) AMD and 180,000 new cases of geographic-atrophy (dry) AMD occur in Canada each year. In 2006, the estimated cost to the Canadian gross domestic product (GDP) was $2.6 billion (1).

AMD is considered a major public health problem, and according to the National Coalition for Vision Health, over one million Canadians are affected by early AMD, with 250,000 individuals being affected with the advanced form of the disease. Unfortunately, this number is expected to double by 2031.  In 2006, there were 64,000 Canadians blind due to AMD.

 Pathology of AMD:

Vision loss in AMD is attributable to photoreceptor death in the central retina. Growing evidence suggests a role for retinal pigment epithelial (RPE) cell damage and death, caused by different mechanisms including inflammation and oxidative stress, causing photoreceptor death and loss of vision (2).

 Dry / Wet AMD:

There are two clinical types of AMD, the “dry” and “wet” form.

In dry AMD, which is the most prevalent form (90%), insoluble extracellular aggregates called drusen accumulate in the retina. Dry AMD causes gradual loss of central vision, but it can eventually develop to the more aggressive wet form. In wet AMD, new immature blood vessels grow underneath the retina, leaking blood and fluid into the retina. Wet AMD is the most severe form of the disease, and can lead to rapid vision loss (2).  Although vision loss due to AMD is becoming a major public health problem, currently there is no therapy option for the dry form of the disease, and medication for wet AMD is expensive and invasive. Therefore, more convenient preventive or therapeutic interventions are needed for reducing this health burden. Since multiple factors are involved in the pathogenesis of AMD, a multi-faceted approach will most likely be required to prevent and treat this disease.

 Resveratrol:

Resveratrol has a diverse range of potential beneficial effects in our body. During the last decade we have seen a growing interest in the effects of resveratrol on the eye, both for disease prevention and treatment.

Resveratrol is the main biologically active polyphenol in red wine, and is also found in red grapes, peanut, Japanese giant knotweed, blueberries, bilberries, and cranberries.

Resveratrol has shown vascular enhancing properties, and it has been suggested to be effective in the microcirculation of the eye, to help prevent or treat ocular diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma.

More specifically, resveratrol has shown promising anti-oxidant, antiapoptotic, anti-tumourogenic, anti-inflammatory, antiangiogenic and vasorelaxant properties.

Impaired blood flow and subsequent ischaemic changes are implicated in the pathology of several ocular diseases including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma, which are common causes of sight loss.

Therefore, resveratrol for it vascular enhancing effects has the potential to prevent the onset and progression of such ocular diseases.

Supplementation with resveratrol has potential benefits across a wide range of ocular diseases via a diverse range of molecular mechanisms.

Anti-oxidant compounds such as resveratrol are able to combine with damaging free radicals, thereby stabilising them and preventing sustained oxidation.

Oxidative stress is thought to be involved in progression of several eye diseases including primary open-angle glaucoma (POAG), a major cause of worldwide irreversible blindness.

Oxidative stress caused cell damage, leading to increased apoptotic cell death. Treatment with resveratrol has shown therapeutic potential in primary open-angle glaucoma (POAG). Resveratrol inhibited the increased production of intracellular reactive oxygen species (iROS), which in turn prevented the induction of the pro-inflammatory markers such as interleukin-1a (IL1a), interleukin-6 (IL-6). Resveratrol also prevented the expression of the cellular senescence marker sa-β-galactosidase (sa-β-gal), which is typically induced by oxidative stress.

Similarly the formation of age-related cataracts is also associated with prolonged oxidative stress, in which oxidation of proteins within the lens is thought to play a crucial role in the pathogenesis of cataracts.

When tested in rat against selenite-induced cataract formation, resveratrol caused an increase in the levels of reduced glutathione (GSH) in rat lenses and erythrocytes. High levels of GSH protect the lens against oxidative damage. GSH levels have been shown to decline in age-related human cataracts and selenite-induced cataracts in rats, suggesting an essential role in preserving lens function. Therefore, resveratrol is suggested for its potential role in preventing development or progression of age-related cataracts in human.

Resveratrol has also shown significant antidiabetic effects, and has been shown to have therapeutic potential for protecting against or preventing diabetic retinopathy (DR). Diabetic retinopathy (DR) is a common problem in both type of diabetes and is a leading cause of acquired blindness. It is believed that hyperglycemia leads to an imbalance between production of reactive oxygen species (ROS) and neutralization of ROS by antioxidants, contributing to the pathogenesis of diabetic retinopathy (DR). Furthermore, treatment with resevratrol has shown beneficial effects in protecting against vessel leakage, pericyte loss, and VEGF protein levels (3).

Resveratrol is a natural nonflavonoid polyphenolic compound found in grapes, red wine, mulberries, knotweed, peanuts and other plants. Similar to crocin, resveratrol could modulate multiple targets involved in development and progression of AMD. It ameliorates function of retinal cells by suppressing factors involved in retinal damage such as caspases, and VEGF (4-5). It also protects retinal cells by enhancing the protective effect of targets such as catalase, heme oxygenase-1, superoxide dismutase (6), and sirtuin-1 (7).

Pre-treatment with resveratrol protects human RPE cells against H2O2-induced cytotoxicity by increasing GSH levels, and enhancing activities of antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. In retinal cells resveratrol inhibits generation of intracellular reactive oxygen species (ROS) under the H2O2-induced stress condition (8). Furthermore, resveratrol protects human RPE cells against acrolein-induced oxidative stress by increasing the mitochondrial bioenergetics (9).

It is widely recognized that inflammation is involved in pathogenesis of AMD. In an EIU mouse model of ocular inflammation (endotoxin-induced uveitis), resveratrol inhibits oxidative damage and suppresses NF-kB activation, leading to ocular anti-inflammatory effect (10).

Resveratrol protects against oxygen-induced retinopathy in retinal cell cultures of neonatal rat by modulating nitric oxide synthase (11).

Resveratrol due to its antiapoptotic and antioxidant properties reverses the loss of cell viability in ARPE-19 cell cultures when challenged with benzo(a)pyrene (B(e)P), a toxic compound from cigarette smoke. Resveratrol inhibits the increased activity of caspase-3/7 and caspase-9, and reduces level of reactive oxygen/nitrogen species (ROS/RNS) in B(e)P-treated cells. Activation of caspase-3/7 is capable of initiating DNA fragmentation, which leads to apoptosis. Activation of caspase-9 is associated with mitochondrial stress, leading to cellular injury (12).

Resveratrol also inhibits tunicamycin-induced ER stress and vascular degeneration in mouse eyes via inhibiting the expression of ER stress markers, CHOP and IRE1 a (12).  Another mechanism that resveratrol protects against light-induced retinal degeneration in mice is by augmenting activity of retinal sirtuin 1 (SIRT1), and by suppressing retinal activator protein-1, which becomes up-regulated upon light exposure. For its multiple functions, resveratrol has been suggested as a therapeutic agent to prevent light-induced retinal degeneration (7).

SIRT1 is a deacylase protein that acts as energy and redox sensor, and helps cells to survive under apoptosis-inducing stress conditions. It influences pathways involved in aging, inflammation, apoptosis and stress resistance.  SIRT1 is present in cells forming all normal ocular structures, including the cornea, lens and retina. Up-regulation of SIRT1 has been shown to have a potent protective effect against retinal degeneration (13).

In human RPE cells amyloid β (Aβ) inhibits SIRT1, induces NF-kB signalling and leads to chronic inflammation, a key factor in development and progression of AMD. Resveratrol inhibits Aβ-induced expression of IL-6, IL-8, and MMP-9, which are involved in chronic inflammation. Resveratrol regulates inflammation by upstream activation of SIRT-1 leading to inhibition of Aβ-mediated activation of NF-kB (Cao et al, 2013).  Activation of SIRT1 by resveratrol prevents retinal ganglion cell (RGC) loss in optic neuritis through reducing oxidative stress and promoting mitochondrial function in a neuronal cell line (14).  A recent report has shown protective effects on sodium iodate-induced RPE cell toxicity via inhibition of ROS and IL-8 production (15).

Antiangiogenic effect of resveratrol:

In several in vitro and in vivo experiments resveratrol has been shown to inhibit proliferation and migration of vascular endothelial cells, suppressing pathological angiogenesis and providing a significant protective effect against the development and/or sustenance of choroidal neovascularization (CNV). For this, resveratrol has been suggested for treating ocular diseases with exuberant and abnormal angiogenesis including AMD(4).

Oxysterols induce VEGF secretion in human retinal cells and can trigger cytotoxic, pro-inflammatory, pro-oxidative and pro-angiogenic activities responsible for AMD lesions. Resveratrol down-regulates VEGF synthesis, and when used at 1 mM prevents neovascularization and cell death caused by oxysterols  (16).   Resveratrol also inhibits VEGF secretion in hypoxia-induced choroidal vascular endothelial cell (CVEC) proliferation, and inhibits laser-induced choroidal neovascularization (CNV) in Brown Norway rats (9).

Recently, a resveratrol-containing oral pill has been tested in patients that refused or failed to respond to intra-vitreal anti-VEGF treatments (Lucentis®, Avastin® or Eylea)

. Resveratrol restored retinal structure and visual function with significant anti-VEGF type effect including anatomic restoration of retinal structure and improvement in choroidal blood flow.  The retinal tissue regeneration by resveratrol is likely to be mediated by survival of endogenously-produced stem cell (18). Resveratrol at a dose of 10 μM suppressed HUVEC proliferation and migration under VEGF stimulation comparable to the effect of bevacizumab (Avastin) 19.

Resveratrol significantly reduces pathological subretinal neovascularization

in a mouse model known as, very low-density lipoprotein receptor (VLDLR) mutant (Vldlr -/-). VEGF is elevated in Vldlr_/_ retina, which shows photoreceptor degeneration. Rresveratrol downregulates VEGF and attenuates response of retinal endothelial cells to angiogenic stimulation. Similar effect has been also shown in an ex-vivo aortic ring assay and in cell culture experiments (20).

Platelet-derived growth factor (PDGF) is another growth factor that exhibits strong chemotactic and proliferative effects on RPE cells in proliferative vitreoretinopathy. Another mechanism for antiangiogenic effect of resveratrol is via inhibition of PDGF-induced RPE migration. Resveratrol, added to drinking water, showed significant inhibition of neovascularization in mouse cornea induced by VEGF and fibroblast growth factor 2 (FGF-2).

As mentioned above resveratrol is thought to prevent progression of ocular diseases including degenerative diseases, such as diabetic retinopathy,age-related macular degeneration (AMD), glaucoma and cataracts. There is no cure for these eye diseases and treatment options are limited and are mainly used to delay the progression of disease.

For individuals that are pre-disposed to development of AMD and diabetic retinopathy, may potentially benefit from by resveratrol supplementation as an early preventative measure.

Future human studies are expected to provide more evidence on mechanism of action of resveratrol and its potential benefits in ocular diseases.

 

 

References:

1-Brown et al,. 2005. Age-related macular degeneration: economic burden and value-based medicine analysis. Can J Ophthalmol. 2005 Jun;40(3):277-87.

2-Sheu et al,. 2010. Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. J Ocul Pharmacol Ther. 2010 Jun;26(3):231-6.

3-Nagineni et al,. 2014. Resveratrol Suppresses Expression of VEGF by Human Retinal Pigment Epithelial Cells: Potential Nutraceutical for Age-related Macular Degeneration. Aging Dis. 2014 Apr 1;5(2):88-100. doi: 10.14366/AD.2014.050088.

4-Khan et al,. 2010. Resveratrol regulates pathologic angiogenesis by a eukaryotic elongation factor-2 kinase-regulated pathway. Am J Pathol. 2010 May;177(1):48-492.

5-Chan et al,. 2013. Inhibitory effects of resveratrol on PDGF-BB-induced retinal pigment epithelial cell migration via PDGFRβ, PI3K/Akt and MAPK pathways. PLoS One. 2013 Feb;8(2):e56819. doi: 10.1371/journal.pone.0056819.

6-Zheng et al, 2010.Resveratrol protects human lens epithelial cells against H2O2-induced oxidative stress by increasing catalase, SOD-1, and HO-1 expression. Mol Vis. 2010 Aug ;16:1467-74.

7-Kubota et al,. 2010. Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation. Am J Pathol. 2010 Aug;177(4):1725-31.

8-Pintea et al,. 2011. Antioxidant effect of trans-resveratrol in cultured human retinal pigment epithelial cells. J Ocul Pharmacol Ther. 2011 Aug;27(4):315-21.

9-Sheu et al,. 2013. Resveratrol stimulates mitochondrial bioenergetics to protect retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci. 2013 Sep;54(9):6426-38. doi: 10.1167/iovs.13-12024.

10-Kubota et al,. 2009. Prevention of ocular inflammation in endotoxin-induced uveitis with resveratrol by inhibiting oxidative damage and nuclear factor-kappaB activation. Invest Ophthalmol Vis Sci. 2009 Mar;50(7):3512-9.

11-Kim and Suh,. 2010. Retinal protective effects of resveratrol via modulation of nitric oxide synthase on oxygen-induced retinopathy. Korean J Ophthalmol. 2010 Apr;24(2):108-18.

12-Li et al,.2012. Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol. Invest Ophthalmol Vis Sci. 2012 May;53(6):3241-9. doi: 10.1167/iovs.11-8406.

13-Mimura et al,. 2013. The role of SIRT1 in ocular aging. Exp Eye Res. 2013 Nov;116:17-26. doi: 10.1016/j.exer.2013.07.017.

14- Khan et al,. 2012. SIRT1 activating compounds reduce oxidative stress and prevent cell death in neuronal cells. Front Cell Neurosci. 2012 Dec;6:63. doi: 10.3389/fncel.2012.00063.

15-Qin et al,. 2013. Resveratrol protects RPE cells from sodium iodate by modulating PPARα and PPARδ. Exp Eye Res. 2013 Dec;118C:100-108. doi: 10.1016/j.exer.2013.11.010.

16-Dugas et al,. 2010. Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol. Eur J Nutr. 2010 Mar; 49(7):435-46.

17-Balaiya et al,. 2013. Resveratrol inhibits proliferation of hypoxic choroidal vascular endothelial cells. Mol Vis. 2013 Nov;19:2385-92.

18-Richer et al,. 2013. Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement. Nutrients. 2013 Jun;5(6):1989-2005. doi: 10.3390/nu5061989.

19-Cao et al,. 2013. SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway. Braz J Med Biol Res. 2013 Aug;46(8):659-69. doi: 10.1590/1414-431X20132903.

20-Hua et al,. 2011. Resveratrol inhibits pathologic retinal neovascularization in Vldlr-/ - Mice. Invest Ophthalmol Vis Sci. 2011 Apr;52(5):2809-26.



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