Protection against UV radiation induced skin damage by methoxylated flavonoids

Project Summary In eukaryotic cells ultra violet radiation UVR induces the formation of free radicals which damage cellular lipids proteins and nucleic acids In man this damage can lead to chronic inflammation and skin neoplasias so that compounds which protect cells from UVR are of therapeutic interest Flavonoids are candidates because they protect plant cells by absorbing UVR and acting as free radical scavengers FRS Bluegrass Advanced Materials BAM has licensed a technology from Naprogenix Inc which is based on the discovery that methoxylated flavonoids purified from extracts of a native goldenrod Solidago nemoralis have agonist activity at human alpha nicotinic receptors nicAChRs These receptors inhibit release of inflammatory mediators from skin macrophages which contribute to UV mediated inflammation and carcinogenesis In support collaborative research with the University of Kentucky showed that a flavonoid enriched goldenrod extract potently protected transgenic humanized mice against UVR induced inflammation and damage in vivo However the potential therapeutic and commercial value of this activity is limited by the modest persistence and bioavailability of these flavonoids when applied topically To overcome this drawback BAM will utilize its proprietary technology to convert flavonoids into biodegradable polymer microparticles These slowly release the original flavonoids from the polymer essentially providing an extended release topical preparation with improved bioavailability This phase I application will apply this technology to the methoxylated anti inflammatory flavonoids and evaluate their microparticle preparation for UV protection when administered topically in a mouse model of the fair skinned UV sensitive human The first specific aim is to prepare microparticle polymers of a the flavonoid enriched extract of goldenrod and b pure rhamnetin the methoxylated flavonoid with greatest potency on alpha nicAChRs The second specific aim is to test each of these preparations for their ability to penetrate and protect humanized mouse skin against UVR specifically measuring the tissue content of pro and anti inflammatory mediators and measuring effects on erythema and inflammation The effects of the microparticle polymers will be compared with those of the free flavonoids applied topically in ethanol polyethylene glycol as used previously If as predicted the UVR protectant effects of the flavonoids are enhanced then phase II will aim to a relate efficacy to alpha nicAChR activity using selective antagonists and alpha nicAChR knockout mice b test the effects of chronic use of the preparations on UVR induced changes in mouse skin c develop new ways of producing these flavonoids The ultimate objectives of phase I and II are to develop these methoxylated flavonoid polymer preparations as therapeutic and cosmeceutical agents The intention is to commercialize these products in phase III in partnership with major pharmaceutical and cosmetics companies Project narrative Natural compounds from plants that protect the skin against damage caused by ultraviolet radiation are of commercial value as cosmetics and therapeutic agents This proposal is to begin the development of flavonoids from a native goldenrod for this purpose The main objective of phase I is to demonstrate that the applicants can produce biopolymer formulations of the flavonoids with a greater ability to be absorbed into the skin and with consequently greater protective actions !