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Phytoestrogen Analogues Targeting Neuroinflammation

Boluda Navarro, Mireia (2017) Phytoestrogen Analogues Targeting Neuroinflammation. Other thesis, University of Huddersfield.

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Abstract

Hyperactivation of microglia is known to trigger the release of inflammatory mediators, which contribute to neurodegenerative disease progression and severity. Targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for these diseases. Estrogens have been shown to improve the symptoms of neurodegenerative diseases by binding to estrogen receptors (ERs) and producing an anti-inflammatory effect by mainly reducing the release of pro-inflammatory cytokines like tumour necrosis factor alpha (TNFα), cytokine IL-6 and IL-1β. Nitric oxide (NO), prostaglandin E2 (PGE2) and their enzymes, the inducible nitric oxide synthase (iNOS) and ciclooxygenase-2 (COX-2), respectively, have also been shown to play a part in neuroinflammation. Isoflavones are phytoestrogens that have been known to display anti-inflammatory effects. Biochanin A (BCA) is an ERβ-selective isoflavone phytoestrogen found in red clover. Formononetin (FMN) is another phytoestrogen found in plant-derived red clover among others. In this research, two BCA and one FMN derivatives and a deoxybenzoin BCA intermediate have been synthesized. These derivatives were then evaluated for anti-inflammatory effect in lipopolysaccharide (LPS) activated BV2 cells microglia. BCA derivatives compound 1, 2 and 3 were synthesized by producing a carbamate group, an esterification reaction and by following the synthesis route of deoxybenzoins, respectively. FMN derivative, compound 4, was synthesized by following the same rationale as for compound 1. Cultured BV2 cells were treated with BCA, FMN, compound 1, 2, 3 and 4 for 24 h after previous stimulation with LPS (100 ng/ml). Supernatants were collected and levels of NO, TNFα, IL-6, IL-1β and PGE2 were measured using ELISA. Further studies were carried out on compound 1 to determine its effects on protein levels COX-2 and iNOS by western blotting. Statistical analysis was performed using one-way ANOVA with post-hoc Student Newman-Keuls test. All compounds produced a significant and concentration dependent reduction in the production of NO. However, FMN, compound 1 and 4 reduced the release of TNFα and IL-6, while BCA only blocked TNFα and compound 2 not only did not show a significant reduction on TNFα but increased IL-6 production. BCA, FMN and compound 4 successfully decreased IL-1β and PGE2. Whilst compound 1 showed no effects and 2 augmented it. On the other hand, compound 1 slightly reduced iNOS and COX-2 expression. Compound 3 proved to be cytotoxic for BV2 cells. Our results suggest that the addition of a carbamate group (compound 1 and 4) to a natural precursor might be a better synthesis strategy than that of the attachment of an ester group (compound 2). Therefore, there is a need for further investigation on the mechanism(s) of action of these compounds and their structure activity relationship in the light of the observed effects on pro-inflammatory mediators.

Item Type: Thesis (Other)
Subjects: R Medicine > R Medicine (General)
Schools: School of Human and Health Sciences
Depositing User: Jonathan Cook
Date Deposited: 09 Jan 2018 14:35
Last Modified: 26 Mar 2018 15:30
URI: http://eprints.hud.ac.uk/id/eprint/34174

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