stilbenes and Macular-Degeneration

It is of great therapeutic significance that disordered function of the vascular endothelium which supply the affected ocular structures plays a major role in the pathogenesis and development of age-related macular degeneration. Chronic inflammation is closely linked to diseases associated with endothelial dysfunction, and age-related macular degeneration is accompanied by a general inflammatory response. According to current concept, age-related macular degeneration is a local manifestation of systemic vascular disease. This recognition could have therapeutic implications because restoration of endothelial dysfunction can restabilize the condition of chronic vascular disease including age-related macular degeneration as well. Restoration of endothelial dysfunction by pharmaacological or non pharmacological interventions may prevent the development or improve endothelial dysfunction, which result in prevention or improvement of age related macular degeneration as well. Medicines including inhibitors of the renin-angiotensin system (converting enzyme inhibitors, angiotensin-receptor blockers and renin inhibitors), statins, acetylsalicylic acid, trimetazidin, third generation beta-blockers, peroxisome proliferator-activated receptor gamma agonists, folate, vitamin D, melatonin, advanced glycation end-product crosslink breaker alagebrium, endothelin-receptor antagonist bosentan, coenzyme Q10; "causal" antioxidant vitamins, N-acetyl-cysteine, resveratrol, L-arginine, serotonin receptor agonists, tumor necrosis factor-alpha blockers, specific inhibitor of the complement alternative pathway, curcumin and doxycyclin all have beneficial effects on endothelial dysfunction. Restoration of endothelial dysfunction can restabilize chronic vascular disease including age-related macular degeneration as well. Considering that the human vascular system is consubstantial, medicines listed above should be given to patients (1) who have no macular degeneration but have risk factors for the disease and are older than 50 years; (2) who have been diagnosed with unilateral age-related macular degeneration in order to prevent damage of the contralateral eye; (3) who have bilateral age-related macular degeneration in order to avert deterioration and in the hope of a potential improvement. However, randomised prospective clinical trials are still needed to elucidate the potential role of these drug treatments in the prevention and treatment of age-related macular degeneration.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Aspirin; Bosentan; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Folic Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infliximab; Lutein; Macular Degeneration; Melatonin; PPAR gamma; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Resveratrol; Stilbenes; Sulfonamides; Trimetazidine; Tumor Necrosis Factor-alpha; Ubiquinone; Vitamin D; Xanthophylls

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.

Topics: Aging; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Bevacizumab; Capillary Permeability; Cholestanols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Design; Drugs, Investigational; Eye Proteins; Humans; Injections; Lactates; Macular Degeneration; Models, Animal; Multicenter Studies as Topic; Neovascularization, Pathologic; Nerve Growth Factors; Pigment Epithelium of Eye; Protein Isoforms; Randomized Controlled Trials as Topic; RNA Interference; RNA, Small Interfering; Serpins; Stilbenes; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vitreous Body

This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).. Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).. The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods.. The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Choroidal Neovascularization; Female; Fever; Headache; Humans; Hypertension; Infusions, Intravenous; Long QT Syndrome; Macular Degeneration; Male; Middle Aged; Pilot Projects; Stilbenes; Treatment Outcome

Resveratrol is a phytoalexin, stilbenoid compound with antioxidant properties attributable to its bioactive

Topics: Aged; Aged, 80 and over; Antioxidants; Cell Line; Cell Nucleus; Cell Survival; Cells, Cultured; Dietary Supplements; Epithelial Cells; Fallopia japonica; Female; Humans; Macular Degeneration; Male; Mitochondria; Oxidative Stress; Plant Extracts; Reactive Oxygen Species; Resveratrol; Retinal Pigment Epithelium; Stilbenes; Vitis

Damage of retinal pigment epithelial (RPE) cells by A2E may be critical for age-related macular degeneration (AMD) management. Accumulation and photooxidation of A2E are known to be one of the critical causes in AMD. Here, we evaluated the protective effect of resveratrol (RES), piceatannol (PIC) and RES glycones on blue-light-induced RPE cell death caused by A2E photooxidation. A2E treatment followed by blue light exposure caused significant damages on human RPE cells (ARPE-19). But the damages were attenuated by post- and pre-treatment of RES and PIC in our in vitro models. The results of cell free system and FAB-MS analysis clearly showed that the reduction of A2E by blue light exposure was significantly rescued, and that oxidized forms of A2E were significantly reduced by RES or PIC treatment. Besides, RES or PIC inhibited the intracellular accumulation of A2E. Not only RES and PIC but RES glycones showed protection of ARPE-19 cells against A2E and blue-light-induced photo-damage. These findings demonstrate that RES and its analogs may have protective effects against A2E and blue-light-induced ARPE-19 cell death through regulation of A2E accumulation as well as photooxidation of A2E. Thus RES and its analogs may be beneficial for AMD treatment.

Topics: Cell Death; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Macular Degeneration; Neuroprotective Agents; Resveratrol; Retinal Pigment Epithelium; Stilbenes

Selective killing of RPE cells in vivo by sodium iodate develops cardinal phenotypes of atrophic age-related macular degeneration. However, the molecular mechanisms are elusive. We tried to search for small cyto-protective molecules against sodium iodate and explore their mechanisms of action. Sodium iodate-mediated RPE cell death was associated with increased levels of reactive oxygen species (ROS) and IL-8. Resveratrol, a natural occurring polyphenol compound, was found to strongly protect RPE cells from sodium iodate with inhibition of production of ROS and IL-8. Resveratrol activated all isoforms of PPARs. Treatment with PPARα and PPARδ agonists inhibited sodium iodate-induced ROS production and protected RPE cells from sodium iodate. A PPARα antagonist significantly reduced resveratrol's protection of RPE cells from sodium iodate. Paradoxically, knocking down PPARδ also rendered RPE cells resistant to sodium iodate. Moreover, PPAR agonists reversed sodium iodate-induced production of IL-8. However, neutralizing extracellular IL-8 failed to protect RPE cells from sodium iodate. Taken together, these observations show that resveratrol protects RPE cells from sodium iodate injury through the activation of PPARα and alteration of PPARδ conformation. PPARα and δ modulators might ameliorate stress-induced RPE degeneration in vivo.

Topics: Angiogenesis Inhibitors; Antioxidants; Cells, Cultured; Cytoprotection; Gene Expression Regulation; Humans; Iodates; Macular Degeneration; PPAR alpha; PPAR delta; Resveratrol; RNA; Stilbenes

Longevinex® (L/RV) is a low dose hormetic over-the-counter (OTC) oral resveratrol (RV) based matrix of red wine solids, vitamin D3 and inositol hexaphosphate (IP6) with established bioavailability, safety, and short-term efficacy against the earliest signs of human atherosclerosis, murine cardiac reperfusion injury, clinical retinal neovascularization, and stem cell survival. We previously reported our short-term findings for dry and wet age-related macular degeneration (AMD) patients. Today we report long term (two to three year) clinical efficacy.. We treated three patients including a patient with an AMD treatment resistant variant (polypoidal retinal vasculature disease). We evaluated two clinical measures of ocular structure (fundus autofluorescent imaging and spectral domain optical coherence extended depth choroidal imaging) and qualitatively appraised changes in macular pigment volume. We further evaluated three clinical measures of visual function (Snellen visual acuity, contrast sensitivity, and glare recovery to a cone photo-stress stimulus).. We observed broad bilateral improvements in ocular structure and function over a long time period, opposite to what might be expected due to aging and the natural progression of the patient's pathophysiology. No side effects were observed.. These three cases demonstrate that application of epigenetics has long-term efficacy against AMD retinal disease, when the retinal specialist has exhausted other therapeutic modalities.

Topics: Aged; Aged, 80 and over; Aging; Dietary Supplements; Female; Humans; Macular Degeneration; Male; Middle Aged; Nutritional Support; Resveratrol; Retina; Stilbenes; Time Factors; Treatment Outcome; Visual Acuity

Retinal pigment epithelial (RPE) cell death occurs early in the pathogenesis of age-related macular degeneration (AMD) and Stargardt's disease. Emerging evidence suggests that all-trans-retinal (atRal) and alternative complement pathway (AP) activation contribute to RPE cell death in both of these retinal disorders. The aim of this study was to investigate the combined effect of atRal and AP activation on RPE cell viability.. RPE cells were treated with atRal and then incubated with a complement-fixing antibody followed by stimulation with C1q-depleted serum to activate AP. Cell viability was assessed by tetrazolium salt and lactate dehydrogenase release assays. Changes in cell surface CD46 and CD59 expression were assessed by flow cytometry. Cells were pretreated with the antioxidant resveratrol, and C1q-depleted serum was incubated with an anti-C5 antibody prior to initiating AP attack to determine the protective effects of antioxidant therapy and complement inhibition, respectively.. Both atRal and AP activation independently caused RPE cell death. When AP attack was initiated following atRal treatment, a synergistic increase in cell death was observed. Following 24-hour atRal treatment, CD46 and CD59 expression decreased, corresponding temporally to increased susceptibility to AP attack. Resveratrol and the anti-C5 antibody both protected against AP-induced cell death following atRal exposure and were most effective when used in combination.. atRal sensitizes RPE cells to AP attack, which may be mediated in part by atRal-induced downregulation of CD46 and CD59. Despite increased susceptibility to AP attack following exposure to atRal, resveratrol and anti-C5 antibody effectively prevent AP-mediated cell death.

Topics: Angiogenesis Inhibitors; Cell Death; Cells, Cultured; Complement Pathway, Alternative; Flow Cytometry; Humans; Macular Degeneration; Male; Middle Aged; Resveratrol; Retinal Pigment Epithelium; Ribonucleotide Reductases; Stilbenes

Rare spontaneous remissions from age-related macular degeneration (AMD) suggest the human retina has large regenerative capacity, even in advanced age. We present examples of robust improvement of retinal structure and function using an OTC oral resveratrol (RV) based nutritional supplement called Longevinex® or L/RV (circa 2004, Resveratrol Partners, LLC, Las Vegas, NV, USA). RV, a polyphenolic phytoalexin caloric-restriction mimic, induces hormesis at low doses with widespread beneficial effects on systemic health. RV alone inhibits neovascularization in the murine retina. Thus far, published evidence includes L/RV mitigation of experimentally induced murine cardiovascular reperfusion injury, amelioration of human atherosclerosis serum biomarkers in a human Japanese randomized placebo controlled trial, modulation of micro RNA 20b and 539 that control hypoxia-inducing-factor (HIF-1) and vascular endothelial growth factor (VEGF) genes in the murine heart (RV inhibited micro RNA20b 189-fold, L/RV 1366-fold). Little is known about the effects of L/RV on human ocular pathology.. Absent FDA IRB approval, but with permission from our Chief of Staff and medical center IRB, L/RV is reserved for AMD patients, on a case-by-case compassionate care basis. Patients include those who progress on AREDS II type supplements, refuse intra-vitreal anti-VEGF injections or fail to respond to Lucentis®, Avastin® or Eylea®. Patients are clinically followed traditionally as well as with multi-spectral retinal imaging, visual acuity, contrast sensitivity, cone glare recovery and macular visual fields. Three cases are presented.. Observed dramatic short-term anti-VEGF type effect including anatomic restoration of retinal structure with a suggestion of improvement in choroidal blood flow by near IR multispectral imaging. The visual function improvement mirrors the effect seen anatomically. The effect is bilateral with the added benefit of better RPE function. Effects have lasted for one year or longer when taken daily, at which point one patient required initiation of anti-VEGF agents. Unanticipated systemic benefits were observed.. Preliminary observations support previous publications in animals and humans. Restoration of structure and visual function in octogenarians with daily oral consumption of L/RV is documented. Applications include failure on AREDS II supplements, refusing or failing conventional anti-VEGF therapy, adjunct therapy to improve RPE function, and compassionate use in medically underserved or economically depressed third-world countries.

Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Asian People; Bevacizumab; Biomarkers; Choroidal Neovascularization; Dietary Supplements; Female; Humans; Macular Degeneration; Male; Ranibizumab; Resveratrol; Retina; Retinal Pigment Epithelium; Stilbenes; Vascular Endothelial Growth Factor A

Resveratrol (RSV) alleviates oxidative damage in human adult retinal pigment epithelial (ARPE) cells. Mitochondrial bioenergetics is associated with oxidative stress. The purpose of this study was to examine the role of mitochondrial bioenergetics in the cytoprotective effect of RSV. Its role in protection against the adverse effects of cigarette smoke (CS) in experimental choroidal neovascularization (CNV) was also examined.. Cultured ARPE-19 cells were treated with acrolein alone or acrolein with added RSV. Temporal changes in cell viability, expression of the antioxidant protein, and mitochondrial bioenergetics were evaluated. In an animal study, CNV lesions were created in Brown Norway rats by laser-induced photocoagulation. Effects of CS alone or with additional RSV treatment on CNV lesions were quantified by fundus fluorescein angiography.. In ARPE-19 cells, RSV rescued acrolein-induced cell death, alongside reversal of acrolein-induced superoxide dismutase expression. Resveratrol increased the mitochondrial bioenergetics, including basal respiratory rate, adenosine triphosphate synthesis via oxidative phosphorylation, and maximal mitochondrial capacity. In animal experiments, CS induced a significant increase in CNV following laser injury, and this increase in CNV was appreciably prevented following peripheral infusion of RSV.. Our results indicate that RSV, a major polyphenol found in red wine, exerts protection against acrolein-induced cytotoxicity in human ARPE-19 cells via increases in the mitochondrial bioenergetics. In addition, the antioxidant effect of RSV may contribute to protection against laser-induced CNV in animals exposed to CS. Therefore, RSV might be beneficial for treatment of acrolein-induced or CS-evoked RPE degeneration.

Topics: Adult; Angiogenesis Inhibitors; Animals; Cell Survival; Cytoprotection; Disease Models, Animal; DNA Damage; Energy Metabolism; Enzyme Inhibitors; Female; Humans; Macular Degeneration; Mitochondria; Oxidative Stress; Rats; Rats, Inbred BN; Resveratrol; Retinal Pigment Epithelium; Stilbenes

Chronic inflammation induced by amyloid-beta (Aβ) plays a key role in the development of age-related macular degeneration (AMD), and matrix metalloproteinase-9 (MMP-9), interleukin (IL)-6, and IL-8 may be associated with chronic inflammation in AMD. Sirtuin 1 (SIRT1) regulates inflammation via inhibition of nuclear factor-kappa B (NF-κB) signaling, and resveratrol has been reported to prevent Aβ-induced retinal degeneration; therefore, we investigated whether this action was mediated via activation of SIRT1 signaling. Human adult retinal pigment epithelial (RPE) cells were exposed to Aβ, and overactivation and knockdown of SIRT1 were performed to investigate whether SIRT1 is required for abrogating Aβ-induced inflammation. We found that Aβ-induced RPE barrier disruption and expression of IL-6, IL-8, and MMP-9 were abrogated by the SIRT1 activator SRT1720, whereas alterations induced by Aβ in SIRT1-silenced RPE cells were not attenuated by SRT1720. In addition, SRT1720 inhibited Aβ-mediated NF-κB activation and decrease of the NF-κB inhibitor, IκBα. Our findings suggest a protective role for SIRT1 signaling in Aβ-dependent retinal degeneration and inflammation in AMD.

Topics: Adult; Amyloid beta-Peptides; Antioxidants; Blood-Retinal Barrier; Cell Survival; Enzyme Assays; Gene Silencing; Heterocyclic Compounds, 4 or More Rings; Humans; Inflammation; Interleukin-6; Interleukin-8; Macular Degeneration; Matrix Metalloproteinase 9; NF-kappa B; Primary Cell Culture; Real-Time Polymerase Chain Reaction; Resveratrol; Retinal Pigment Epithelium; RNA Interference; Signal Transduction; Sirtuin 1; Stilbenes