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Title: The effect of dietary-relevant concentrations of flavonoids on neuroprotective pathways in astrocytes
Author: Spilsbury, Alison
ISNI:       0000 0004 2743 014X
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2012
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Neuroinflammation plays an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PO). Sustained activation of nuclear transcription factor KB (NF-KB) is thought to play an important role in the pathogenesis of neurodegenerative disorders. Activation of the NF-KB pathway in astrocytes may elicit a pro-inflammatory response through increased production and secretion of cytokines such as IL-1, IL-6, TNFa and IFN-y and of nitric oxide. Through secretion of these molecules, astrocytes may injure surrounding neurons. Glutathione is the body's predominant defence against oxidative species, and glutathione dysregulation is linked to numerous neurodegenerative diseases including; AD, PO, Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease. Flavonoids have been shown to possess antioxidant and anti-inflammatory properties both in vivo and in vitro, mainly through their capacity to modulate a number of intracellular signalling pathways. This study investigated whether different classes of flavonoids were able to modulate NF-KB signalling and the glutathione system in embryonic mouse cortical astrocytes. Using luciferase reporter assays and immunocytochemistry, it was found that astrocytes display functional NF-KB activity which may be induced by TNFa (150 ng/mL), leading to increased NF-KB-mediated transcription and nuclear localisation of p65. Bacterial Lipopolysaccaride (LPS) treatment did not increase NF-KB activity, but resulted in nuclear localisation of p65. Astrocytes also display a functional glutathione system, which was stimulated using tBHQ. To investigate potential flavonoid modulation of NF-KB activity and intracellular glutathione levels, astrocytes were treated with flavonoids from different classes; ftavan-a-ols ((-)-epicatechin and (+)- catechin), flavones (Iuteolin and chrysin), flavonol (kaempferol) or flavanones (naringenin and hesperetin) at dietary-relevant concentrations (0.1 - 1 I-IM) for 18 h. None of the flavonoids modulated constitutive or TNFa-induced NF-KB activity. Kaempferol significantly increased intracellular glutathione levels. Therefore, we conclude that the astrocyte glutathione system is a target for kaempferol at these concentrations. However, dietary-relevant concentrations of flavonoids do not modulate NF-KB activity in astrocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available