Anti-diabetic and neuroprotective activities of phytochemicals in traditionally used boreal plants

Title: Anti-diabetic and neuroprotective activities of phytochemicals in traditionally used boreal plants
Authors: Harris, Cory S
Date: 2008
Abstract: This thesis investigated the phytochemistry and pharmacology of boreal plant species used traditionally as treatments for symptoms and complications of diabetes and was completed in collaboration with the Team in Aboriginal Anti-Diabetic Medicine and the Cree of Eeyou Istchee in northern Quebec. Using a novel metabolomic-based approach, we first developed methods of phytochemical analysis to characterize Vaccinium angustifolium extracts and then other medicinal Ericaceae, identifying and quantifying an abundance of phenolic compounds. These methods were then employed to profile the phenolics in anti-diabetic species identified by Cree Elders. Pharmacological assays of extracts focused primarily on in vitro inhibition of mechanisms involved in the pathophysiology of diabetic neuropathy, associated diabetic complications and neurodegenerative conditions. Upon testing for cytoprotective effects in two models of diabetic neuropathy, few extracts prevented cell loss mediated by serum/glucose deprivation but 10 of 18 significantly reduced glucotoxic cell death. The activities of Picea glauca needles, which was cytoprotective in both models, and Sarracenia purpurea leaves were of particular interest as observed organ-specific effects correlated with medicinal uses identified by Cree Elders. Cytoprotection, however, did not correlate with extract phenolic content or anti-oxidant activity. Active principles were therefore sought through assay-guided fractionation of S. purpurea extract, identifying quercetin-3- O-galactoside, which inhibited glucotoxicity at low micromolar concentrations. Extracts were then tested for effects on formation of advanced glycation endproducts. Most displayed concentration-dependent inhibition with IC50 values ranging from 0.4-38.6 mug/ml. Anti-glycation activity was significantly correlated with extract phenolic content and anti-oxidant capacity. The bioactivities of individual phenolic metabolites were then evaluated at physiologically relevant concentrations using molecular tools to determine cell proliferation, survival and death. A wealth of anti-apoptotic and mitogenic effects were observed and structure-activity relationships were separately identified among benzoic acid derivatives and flavonoids. To explore the neuroprotective potential of these two phenolic classes, collections of each were tested for the ability to inhibit platelet-activating factor (PAF) neurotoxicity. Three novel PAF inhibitors were identified, orsellinic acid, hesperetin and quercetin, and all prevented PAF-mediated executioner caspase activation. Together, these results validate the traditional knowledge shared by our Cree collaborators and highlight the multidimensional therapeutic potential of boreal plants as culturally appropriate complementary anti-diabetic therapies.
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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