Lepiarz-Raba, Izabela (2020) Anti-Inflammatory and Neuroprotective Properties of Isoflavones Analogues. Doctoral thesis, University of Huddersfield.

Chronic neuroinflammation leads to excessive production of pro-inflammatory mediators and consequently neurodegeneration. The alleviation of neuroinflammation may mitigate neurodegenerative disorders, including AD which incidence is higher in women due to decrease of oestrogen during menopause. This hypothesis indicates oestrogens as important neuroprotective factors. However, they may cause detrimental side effects in periphery. Therefore, oestrogens can be substituted by natural compounds such as isoflavones which resemble oestrogen structure but lack detrimental side effects. Presented research investigated anti-inflammatory and neuroprotective properties of four novel isoflavone analogues: biochanin A derivatives with carbamate and dodecenoyl ester moiety (compounds 1 and 2) and daidzein derivatives with ethyl ester and chloropropyl triazole moiety (compounds 3 and 4). The research concluded that compounds 1, 2, 3 and 4 reduced LPS-upregulated levels of TNFα, IL-6, IL-1β, NO and iNOS in BV2 microglia. Biochanin A derivatives were less effective in inhibition of pro-inflammatory cytokines compared to daidzein derivatives. All tested compounds did not affect LPS-induced production of COX-2 and PGE2 and do not possess free radical scavenging properties. Only compound 4 decreased NF-κB activity. All tested compounds did not reduce phosphorylation of p38, JNK and ERK1/2 and upregulated ERE activity. Moreover, the anti-inflammatory properties of compounds 3 and 4 are Nrf2-, SIRT1- and ER-independent. Compounds 3 and 4 diminished H2O2-induced apoptosis in SH-SY5Y neuroblastoma and reduced caspase-3/-7 and -9 activity. Compound 3 upregulated Bcl-2 level. In summary, compounds 3 and 4 inhibited neuroinflammation and protected neurons against oxidative damage. Additionally, this study investigated the validity of HMC3 cells as a cellular model to study neuroinflammation. Amongst ODN 2006, IFNγ, LPS, and TNFα, TNFα induced the broadest inflammatory response in HMC3, upregulating Iba1, IL-6, and activating NF-κB and p38 signalling pathways. HMC3 microglia express ERα and ERβ therefore this cell line can be used to investigate properties of anti-inflammatory compounds acting via ERs.

FINAL THESIS - Lepiarz-Raba.pdf - Accepted Version
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