Age-related Macular Degeneration (AMD)
Diseases

BILBERRY, BLUEBERRY AND CRANBERRY ANTHOCYANINS IN AGE RELATED MACULAR DEGENERATION PREVENTION AND CURE. CAN THEY ACTUALLY BE USED?

Luigi Corvetti and Enrico Frola

INTRODUCTION

Nutraceuticals are diet supplements that deliver a concentrated form of a presumed bioactive agent from a food, presented in a non-food matrix, and used with the purpose of enhancing health in dosages that exceed those that could be obtained from normal foods [ Regulation of ''nutraceuticals'', 1999 ].
Surfing on the web it is possible to find several web sites, often commercial, claiming that cranberry, bilberry or blueberry could be very useful to cure oxidative stress related diseases included age related macular degeneration (AMD). Many of them offer the possibility to buy the extract of these fruits presented in form of pills, as nutraceuticals.
This is just a selection:

• vitalhealthzone
• altmedicine
• lef
• jamiesonvitamins
• greenbush
• vrp
• italian.alibaba

Here we evaluated the scientific literature available on this topic to critically evaluate whether there are enough data supporting the idea of introducing derivatives of these fruits (juice, dried fruits etc.) in the cure of AMD.

Anthocyanins, one class of non-vitamin dietary antioxidants, are abundant in many fruits and vegetables and are known to be potent antioxidants [ The molecular basis for the pharmacological activity of anthocyans, 2011 ]
In the nervous system, vitamin and non-vitamin dietary antioxidants, including anthocyanins, have been shown to improve motor and cognitive functions in experimental animals [ Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats, 2000 ] to prevent ROS-mediated apoptotic death in neurons [ Cyanide enhancement of dopamine-induced apoptosis in mesencephalic cells involves mitochondrial dysfunction and oxidative stress, 2007 ] and to protect retina from oxidative stress damage [ Anthocyanins protect against A2E photooxidation and membrane permeabilization in retinal pigment epithelial cells, 2000 ].
Different kinds of berries have been indicated as a source of anthocyanins and many authors have investigated on the concentration of anthocyanins in the fruits.
However, despite the enormous amount of advise and advertisement on non-specialized web sites about the use of bilberry and/or blackberry to prevent AMD and other retinopathies, scientific data about that are relatively poor.
The ability of bilberry and blueberry extracts to protect the retina from the oxidative stress has been shown on animals, in in vitro and in vivo experiments.
In 2009 Nozomu Matsunaga and colleagues [ Bilberry and its main constituents have neuroprotective effects against retinal neuronal damage in vitro and in vivo, 2009 ] tested the ability of bilberry, and some anthocyanins, known to be its component, to protect retinal neurons in both and in vitro and in vivo models of retinal diseases.
To this aim they first induced a cell damage and radical activation on retinal ganglion cells, cultivated in vitro, by using SIN-1, a peroxynitrite donor, then observed the mortality of cells with or without bilberry extract or the isolated anhocyanis. A similar analyses was done in vivo where the retinal damage was provoked through an intravitreal injections of NMDA. Also in this case the ability of bilberry extract or the isolated anhocyanis was assessed. They found a statistically significative neuroprotective effect induced by the both the bilberry extract and the isolated anhocyanis.
François Tremblay in 2012 [ Prophylactic neuroprotection by blueberry-enriched diet in a rat model of light-induced retinopathy, 2012 ] showed that a prophylactic blueberry-enriched diet is neuroprotective in a model of light-induced retinopathy in rats. For this research they fed a group of rats with a blueberry-enriched diet than provoked a light induced retinal damage. They found that a blueberry-enriched diet is protective to retinal structure in a model of light-induced retinopathy in rats and this kind of diet does not provide protection against light-induced retinopathy once the cascade of retinal damage has been initiated. Furthermore, different breeds of rats demonstrate different susceptibility to the neuroprotective effect of blueberries.

IN CONCLUSION

Data on the use of bilberry, blueberry and blackberry in preventing oxidative stress-related retinopathies are encouraging. However, the mechanism of protections against ROS is still unclear. At the moment, we were not able to find any data on their role on humans, for example a randomized clinical trial as well as their dosage and efficacy in AMD in relation to safety, tolerability, pharmacokinetics and pharmacodynamics, are still lacking. Thus, in our opinion, people should carefully evaluate the opportunity to include berry-containing neutracticals in their diet to prevent or cure AMD, for several reasons. In fact, data about their actual effectiveness are very poor, and based only on few experiments conducted on animals, and, overmore, data on the safety of these neutraceuticals are still absent and it is unknown whether they are well tolerated by our organism.
Our conclusion is supported by other authors, among these Espin and colleagues [ Nutraceuticals: facts and fiction, 2007 ] and Helena Sin and colleagues [ Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration, 2012 ] that say that more clinical trials are required for concrete recommendations on their use.

AMD and prevention

In addition to strong age-dependence of the disease, a complex interaction of metabolic, functional, genetic and environmental factors seems to create a stage for chronically developing changes in ocular structures of the macular region (choriocapillaries, Bruch’s membrane, retinal pigment epithelium-RPE, photoreceptors) which may contribute to varying degrees to the onset and final picture of AMD.
Two subgroups of AMD are classically distinguished:
- atrophic ( dry form)
- exudative ( wet form).
The dry form (also known as geographic atrophy, both central and/or non-central) is typically characterized by a progressing course leading to degeneration of RPE and photoreceptors.
The exudative form is linked to choroidal neovascularization directed to the subretinal macular region, with subsequent bleeding and/or fluid leakage, which may result in a sudden loss of central vision; it is the most rapidly progressing form of AMD.
(Age-related macular degeneration (AMD): pathogenesis and therapy, 2006)

Cumulative oxidative stress and local inflammation are thought to represent pathological processes involved in the etiology of atrophic AMD. Studies of tissue culture and animal models reveal that oxidative stress-induced injury to the RPE results in a chronic inflammatory response, drusen formation, and RPE atrophy. RPE degeneration in turn causes a progressive degeneration of photoreceptors, leading to the irreversible loss of vision.
(Progress and perspectives on the role of RPE cell inflammatory responses in the development of AMD, 2008)

Four processes: lipofuscinogenesis, drusogenesis, inflammation and neovascularization, specifically contribute to the development of two forms of AMD, the dry form (non-exudative; geographic atrophy) and the wet form (exudative, neovascular).
(Age-related macular degeneration (AMD): pathogenesis and therapy, 2006)

Aging of retinal pigment epithelial (RPE) cells of the eye is marked by accumulations of bisretinoid fluorophores; two of the compounds within this lipofuscin mixture are A2E and all-trans-retinal dimer. These pigments are implicated in pathological mechanisms involved in some vision-threatening disorders including age-related macular degeneration (AMD). (A novel source of methylglyoxal and glyoxal in retina: implications for AMD, 2012)

DAMP (damage-associated molecular patterns) molecules can be in general divided into two categories, intracellular and extracellular DAMPs, based on their origin and mechanism of action. Intracellular DAMPs are bioactive mediators of cellular origin that directly stimulate cells of the innate immune system. Extracellular DAMPs are the cleaved fragments of extracellular components generated by enzymes released from dead cells.
In addition to the physiological oxidative stress, aging and pathological conditions can also contribute to oxidative damage to macromolecules via a reduction in defense mechanisms or an increase in ROS production or both. Environmental factors such as cigarette smoke, light exposure, diet, and cataract surgery also enhance ROS generation and can increase the risk for AMD.
(Progress and perspectives on the role of RPE cell inflammatory responses in the development of AMD, 2008)

Prevention

The progressive nature of atrophic AMD and the extensive cell damage in affected individuals at the time of diagnosis indicates that the future of atrophic AMD therapeutics is in the prevention of progression of the disease. Any drug for disease prevention needs to fulfill two crucial requirements. First, the drug should target a key mechanism responsible for the initiation or progression of the disease process. Second, the drug should have minimal side effects and be tolerated for extended periods. To date no such therapy is available for atrophic AMD. Thus, educating people about the risk factors associated with this disease such as smoking and diet is an important consideration at present.
(Progress and perspectives on the role of RPE cell inflammatory responses in the development of AMD, 2008)

Micronutrients play an important role in function and health maintenance for the eye. Especially lutein, zeaxanthin and omega-3 fatty acids perform remarkable functions: lutein together with zeaxanthin forms the macular pigment, these carotenoids filter out the damaging blue light component from the sunlight as well as the ultraviolet light which leads to improved contrast sensitivity and less problems with screen glare. Furthermore, the macular pigment has antioxidant and anti-inflammatory effects. The omega-3 fatty acids also possess anti-inflammatory effects and, when converted into neuroprotectin, they protect against oxidative induced apoptosis in the retina. They are also responsible for the fluidity and supply to the photoreceptor membrane. These properties are important for the prevention and treatment of degenerative eye diseases like AMD.
Scientific studies have shown the positive effects of supplementation with micronutrients such as lutein/zeaxanthin, vitamin C, vitamin E, zinc and omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid (DHA and EPA).
(Micronutrients and their relevance for the eye--function of lutein, zeaxanthin and omega-3 fatty acids, 2011)

Le vitamine antiossidanti A, C ed E sono in grado di svolgere un ruolo profilattico nei confronti del danno maculare legato all'età.
I carotenoidi proteggono l'area maculare, mentre gli acidi grassi omega3 sono fondamentali per le foro funzioni strutturali.
Nell'ambiente extracellulare, nel citoplasma e nei mitocondri la superossido dismutasi che contiene zinco e richiede la presenza di selenio come cofattore, elimina l'anione superossido e lo trasforma in ossigeno e perossido d'idrogeno. Anche la vitamina E è in grado di neutralizzare i radicali liberi, in particolare il radicale idrossile e l'anione superossido. Localizzata nello strato fosfolipidico della membrana cellulare, questa vitamina preleva un elettrone dagli acidi grassi polinsaturi ossidati passando da tocoferolo a tocoferile; in seguito viene "riattivata" dalla vitamina C. (http://www.oftal.it/maculare.htm)

Omega-3

Numerous human studies have assayed a potential relationship between dietary lipids and the development of AMD. The evidence suggests that consumption of omega-3 fatty acids, perhaps in concert with antioxidants, may constitute a rational preventative strategy against AMD development.
(Lipids and age-related macular degeneration, 2011)

Omega-6/omega-3 ratio is connected with development of neovascular ARMD. Decreased ratio protects against neovascular ARMD. On the contrary, GA (geographic atrophy) seems to be connected with prolonged sunlight exposure (the ratio is about 6:1). It is good to know that changing nutrition habits someone can prevent development of severe neovascular form of ARMD because intravitreal anti-VEGF therapy limitations.
(The role of omega6 to omega3 ratio in development and progression of AMD, 2011)

High dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in patients with high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD.
(Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids: the Rotterdam study, 2011)

Other examples of studies:

- (Australia, Dietary omega-3 fatty acid and fish intake in the primary prevention of AMD, 2008)

- (Maryland, The impact of fish and shellfish consumption on AMD, 2010)

- (Harvard Medical School, Boston, Lipids and AMD, 2011)