@phdthesis{Gunesch2021,
  author    = {Gunesch, Sandra},
  title     = {Molecular Mode of Action of Flavonoids: From Neuroprotective Hybrids to Molecular Probes for Chemical Proteomics},
  doi       = {10.25972/OPUS-23936},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239360},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {Alzheimer's disease (AD) is the most common form of dementia, and currently, there is no treatment to cure or halt disease progression. Because the one-target strategy focusing on amyloid-β has failed to generate successful pharmaceutical treatment, this work studies natural products with pleiotropic effects focusing on oxidative stress and neuroinflammation as key drivers of disease progression. The central part of this work focused on flavonoids as neuroprotectants. 7-O-Esters of taxifolin and cinnamic or ferulic acid were synthesized and investigated towards their neuroprotective potential addressing aging and disease. 7-O-Feruloyl- and 7-O-cinnamoyltaxifolin showed overadditive effects in oxidative stress-induced assays in the mouse neuronal cell line HT22 and proved to be protective against neuroinflammation in microglial BV-2 cells. The overadditive effect translated to animals using an Aβ25-35-induced memory-impaired AD mouse model where the compounds were able to ameliorate short-term memory defects. While the disease-modifying effects in vivo were observed, the detailed mechanisms of action and intracellular targets of the compounds remained unclear. Hence, a chemical probe of the neuroprotective flavonoid ester 7-O-cinnamoyltaxifolin was developed and applied in an activity-based protein profiling approach. SERCA and ANT-1 were identified as potential targets. Further, chemical modifications on the flavonoids taxifolin, quercetin, and fisetin were performed. The achievements of this work are an important contribution to the use of secondary plant metabolites as neuroprotectants. Chemical modifications increased the neuroprotective effect of the natural products, and distinct intracellular pathways involved in the neuroprotective mechanisms were identified. The results of this work support the use of secondary plant metabolites as potential therapeutics and hint towards new pharmacological targets for the treatment of neurodegenerative disorders.},
  subject      = {Alzheimerkrankheit},
  language  = {en}
}
@phdthesis{Dreiseitel2011,
  author    = {Dreiseitel, Andrea},
  title     = {In vitro bioactivities of dietary anthocyanins and proanthocyanidins: implications for bioavailability, neuroprotection and safety},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-57550},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Over the past decades, awareness has increased of multiple health-promoting effects of diets rich in anthocyanins and proanthocyanidins and, specifically, of these compounds' potential for conferring neuroprotection. The present study compiles evidence obtained in vitro that expands our understanding of anthocyanin and proanthocyanidin functionalities at multiple levels. Firstly, anthocyanin and anthocyanidin bioavailability was addressed using a combination of ATPase assays, dye extrusion assays and vesicular transport assays. This approach highlights the contribution made by efflux transporters MDR1 and BCRP to the absorption of berry polyphenols and to their distribution to target tissues including the central nervous system. All test compounds interacted with the BCRP transporter in vitro, seven emerged as potential BCRP substrates and 12 as potential inhibitors of BCRP. Two anthocyanidins, malvidin and petunidin, exhibited bimodal activities, serving as BCRP substrates at low micromolar concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak, as only aglycones exerted mild inhibitory activity in the high micromolar range. Distinct affinities of several anthocyanins and the respective aglycones for BCRP suggest that they may be actively transported out of endothelia. Agents that interfere with BCRP activity are therefore likely to facilitate crossing of the intestinal and blood-brain barriers and to augment anthocyanin bioavailability. Secondly, novel modes of action were sought to rationalize berry polyphenols' direct modulation of neuronal transmission as opposed to their non-specific antioxidant activities. The candidate effectors include cellular monoamine oxidases (MAO) A and B, hypoxia inducible factor (HIF), the proteasome, and phospholipase A2 (PLA2). Elevated MAO activity has long been implicated in the etiology of depression, anxiety and neurodegenerative illness. MAO inhibiting compounds may thus hold promise in the prevention of behavioral symptoms and cognitive decline. For both MAO isoforms, inhibitory effects of anthocyanins and anthocyanidins are illustrated by IC50 values in the low micromolar range whereas proanthocyanidins and phenolic metabolites were less effective inhibitors. Kinetic analyses, performed with cyanidin and cyanidin-3-glucoside, indicated a competitive interaction of cyanidin in terms of MAO A, plus a mixed competitive and non-competitive mode of interaction of cyanidin in terms of MAO B as well as of cyanidin-3-glucoside with respect to both enzyme isoforms. Thus MAO inhibition by anthocyanins and their aglycones in vitro lends support to central nervous functionalities of diets rich in berry polyphenols and opens new opportunities in the prevention of neuronal pathologies. Effects on HIF expression were examined to assess candidate compounds' role in enhancing cellular resistance to oxidative stress. By inducing a dose-dependent increase in HIF expression, delphinidin may initiate a variety of cellular survival processes that are inhibited by free iron. This finding argues in favor of iron-chelating properties as a further means of mediating neuroprotection. Other inducers of HIF expression in neuroblastoma cells included gallic acid, cyanidin and bilberry extract, all of which may modulate HIF-dependent transcription of downstream genes.},
  subject      = {Anthocyane},
  language  = {en}
}