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Modulation of multiple neuroinflammatory signalling pathways by the dietary glycosidic flavonoid tiliroside

Velagapudi, Ravikanth (2016) Modulation of multiple neuroinflammatory signalling pathways by the dietary glycosidic flavonoid tiliroside. Doctoral thesis, University of Huddersfield.

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Abstract

Hyperactivated microglia plays a key role in regulating neuroinflammatory responses which propagate damage to neurons. In recent years, substantial attention has been paid in identifying new strategies to abrogate neuroinflammation. Tiliroside, a dietary glycosidic flavonoid found in several medicinal and dietary plants is known to possess anti-inflammatory and antioxidant activities. This study is aimed at investigating the molecular mechanisms involved in the inhibition of neuroinflammation by the tiliroside.

Neuroinflammation inhibitory effects of tiliroside (2-6 μM) were investigated in BV2 microglia stimulated with a combination of LPS (100 ng/ml) and IFN (5 ng/ml). Results show that tiliroside significantly reduced the production of pro-inflammatory cytokines IL-6, TNFα, IL-1β while increasing the production of anti-inflammatory cytokine IL-10 in LPS/IFN-stimulated BV2 microglia. The compound reduced NO production in LPS/IFN-stimulated BV2 cells through inhibition of iNOS protein expression. Tiliroside also suppressed COX-2 protein expression and inhibited PGE2 production in activated microglia. Western blotting and functional experiments revealed that inhibition of neuroinflammation by tiliroside was shown to be mediated through inhibition of NF-B and p38 MAPK signalling pathways. Also, the compound activated SIRT1 and inhibited the expression of acetylated-NF-B-p65 in LPS/IFN-activated BV2 microglia. Further experiments revealed that inhibition of neuroinflammation by tiliroside is not dependent on SIRT1. Tiliroside increased the levels of Nrf2, HO-1 and NQO1 antioxidant proteins, indicating an activation of the Nrf2 protective mechanisms in the microglia. Furthermore, transfection of BV2 cells with Nrf2 siRNA resulted in the loss of anti-inflammatory activities of tiliroside. Results of neurotoxicity experiments showed that neuroinflammation-induced neurodegeneration, DNA fragmentation, ROS generation and calcium accumulation were significantly reduced in HT22 neurons when exposed to conditioned medium from BV2 microglia that were pre-treated with tiliroside prior to stimulation with LPS/IFN.

Results from this study suggest that tiliroside inhibits neuroinflammation in LPS/IFN-activated BV2 microglia by targeting NF-B and p38 MAPK signalling pathways. Furthermore, the compound activated Nrf2 antioxidant mechanisms in the microglia, which appears to contribute to its anti-inflammatory activity. The study also established that tiliroside protects HT22 neurons from neuroinflammation-induced toxicity.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Schools: School of Applied Sciences
Depositing User: Sally Hughes
Date Deposited: 13 Mar 2017 12:55
Last Modified: 13 Mar 2017 19:10
URI: http://eprints.hud.ac.uk/id/eprint/31501

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