Macular Degeneration Research - Completed Award
Nawajes Mandal, Ph.D.
University of Oklahoma Health Sciences Center
Oklahoma City, OK
Title: Nutritional Supplement Of Phytochemical In Prevention Of AMD
Non-Technical Title: Nutraceuticals In Prevention Of AMD
Duration: April 1, 2009 - March 31, 2012
Award Type: Standard
Award Amount: $100,000
The efficacy of known potent anti-inflammatory and anti-oxidative botanical compounds such as, curcumin, sulforaphane, and caffeic acid phenethyl ester (CAPE) will be tested in animal models of retinal degeneration. The protective effect of these compounds on cell death will also be tested in cultured retina-derived cells. The mechanism of action of these compounds in retinal protection will be determined. As age-related macular degeneration (AMD) develops from oxidative-stress and chronic inflammation, we hope to find a promising compound that can be tested further in pre-clinical and clinical trials.
Age-related macular degeneration (AMD) is a multifactorial disease associated with age. It is therefore extremely challenging to develop effective therapies against AMD. Research has identified that oxidative stress and inflammation are integral to the cause, development and effects of AMD. Nutritional supplementation of anti-inflammatory and anti-oxidative compounds holds promises for the least costly and most practical way to delay the onset of AMD and thus protect vision. We have, therefore, selected three botanical compounds which have been in human consumption for hundreds of years as traditional medicines and have been shown to possess potent anti-inflammatory and anti-oxidative properties. As the compounds are plant-derived and non-toxic at fairly high doses, discovering their role in retinal protection will pave the way for clinical trial of a promising compound for augmentative therapy of AMD.
In this project, we will:
1) determine the protective role of curcumin (from Turmeric), sulforaphane (from Broccoli), and caffeic acid phenethyl ester (from Honeybee propolis) in acute and chronic models of light-induced retinal degeneration in rats; and
2) determine the mechanism(s) of curcumin-, sulforaphane-, and caffeic acid phenethyl ester-mediated protection of retina from light-induced damage, and retinal cell lines (661W, ARPE-19) from oxidant-induced damage.
This project will open up new directions for testing the efficacy of other derivatives of these compounds or other promising compounds which may provide better protection from AMD when supplied through diet.
Chen H, Tran JT, Anderson RE, Mandal MN. Caffeic acid phenethyl ester protects 661W cells from H(2)O(2)-mediated cell death and enhances electroretinography response in dim-reared albino rats. Mol Vis. 2012;18:1325-38. Epub 2012 May 30.
Anderson, R.E. and Mandal, M. N. (2009) Anti-Oxidant and Anti-Inflammatory Compounds in Retinal Degeneration, from Molecular Mechanisms to Therapeutic Strategies. Paper presented at 8th International Symposium on Ocular Pharmacology and Therapeutics, Dec 3-6, 2009, Rome, Italy.
Dr. Mandal’s team has determined that dietary supplements made of plant-derived natural compounds—such as curcumin (from turmeric), sulforaphane (SF, from cruciferous vegetables such as broccoli), and caffeic acid phenethyl ester (CAPE, from honeybee propolis)—have protective effects on the retina of rats that have been stressed with intense light exposure (a model of AMD). Curcumin and sulforaphane showed better protection than CAPE. However, CAPE preserved retinal function in rats.
In order to understand how these compounds exert their protective function, the team applied the above-mentioned compounds to mouse retina cells cultured in plates. Following this pre-treatment, the cells were exposed to oxidant stress. Then the team studied their mechanism of action using several biochemical and molecular methods. Pretreatment with curcumin as well as CAPE significantly induced an enzyme (protein) called “Heme Oxygenase 1,” even without applying oxidant stress. Heme Oxygenase 1 is a potent defense molecule against oxidant and inflammatory stress. When Dr. Mandal’s team fed curcumin to rats, this supplement inhibited activation of a protein called NFkB, activation of which is responsible for inducing inflammation and cell death in the retina. A compound that has potential to induce cellular defense mechanism against oxidative stress and inflammation may have tremendous therapeutic possibilities as a supplement for nutritional and augmentative therapy of AMD.