The tiliroside derivative, 3-O-[(E)-(2-oxo-4-(p-tolyl) but-3-en-1- yl] kaempferol produced inhibition of neuroinflammation and activation of AMPK and Nrf2/HO-1 pathways in BV-2 microglia

Ravikanth Velagapudi, Faisal Jamshaid, Izabela Lepiarz-Raba, Folashade Katola, Karl Hemming, Olumayokun Olajide

Research output: Contribution to journalArticle

Abstract

Neuroinflammation is now widely accepted as an important pathophysiological mechanism in neurodegenerative disorders, thus providing a critical target for novel compounds. In this study, 3-O-[(E)-(2-oxo-4-(p-tolyl)but-3-en-1-yl] kaempferol (OTBK) prevented the production of pro-inflammatory mediators TNFα, IL-6, PGE 2 and nitrite from BV-2 microglia activated with LPS and IFNγ. These effects were accompanied by reduction in the levels of pro-inflammatory proteins COX-2 and iNOS. Involvement of NF-κB in the anti-inflammatory activity of OTBK was evaluated in experiments showing that the compound prevented phosphorylation, nuclear accumulation and DNA binding of p65 sub-unit induced by stimulation of BV-2 microglia with LPS and IFNγ. Exposure of mouse hippocampal HT22 neurons to conditioned media from LPS + IFNγ-stimulated BV-2 cells resulted in reduced cell viability and generation of cellular reactive oxygen species. Interestingly, conditioned media from LPS/IFNγ–stimulated BV-2 cells which were treated with OTBK did not induce neuronal damage or oxidative stress. OTBK was shown to increase protein levels of phospho-AMPKα, Nrf2 and HO-1 in BV-2 microglia. It was further revealed that OTBK treatment increased Nrf2 DNA binding in BV-2 microglia. The actions of the compound on AMPKα and Nrf2 were shown to contribute to its anti-inflammatory activity as demonstrated by diminished activity in the presence of the AMPK antagonist dorsomorphin and Nrf2 inhibitor trigonelline. These results suggest that OTBK inhibits neuroinflammation through mechanisms that may involve activation of AMPKα and Nrf2 in BV-2 microglia.

Original languageEnglish
Article number105951
JournalInternational Immunopharmacology
Volume77
Early online date18 Oct 2019
DOIs
Publication statusPublished - 1 Dec 2019

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AMP-Activated Protein Kinases
Microglia
Conditioned Culture Medium
Anti-Inflammatory Agents
DNA
Nitrites
Prostaglandins E
Neurodegenerative Diseases
Interleukin-6
Reactive Oxygen Species
Cell Survival
Proteins
Oxidative Stress
Phosphorylation
kaempferol
tiliroside
Neurons

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title = "The tiliroside derivative, 3-O-[(E)-(2-oxo-4-(p-tolyl) but-3-en-1- yl] kaempferol produced inhibition of neuroinflammation and activation of AMPK and Nrf2/HO-1 pathways in BV-2 microglia",
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The tiliroside derivative, 3-O-[(E)-(2-oxo-4-(p-tolyl) but-3-en-1- yl] kaempferol produced inhibition of neuroinflammation and activation of AMPK and Nrf2/HO-1 pathways in BV-2 microglia. / Velagapudi, Ravikanth; Jamshaid, Faisal; Lepiarz-Raba, Izabela; Katola, Folashade; Hemming, Karl; Olajide, Olumayokun.

In: International Immunopharmacology, Vol. 77, 105951, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Jamshaid, Faisal

AU - Lepiarz-Raba, Izabela

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AU - Hemming, Karl

AU - Olajide, Olumayokun

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AB - Neuroinflammation is now widely accepted as an important pathophysiological mechanism in neurodegenerative disorders, thus providing a critical target for novel compounds. In this study, 3-O-[(E)-(2-oxo-4-(p-tolyl)but-3-en-1-yl] kaempferol (OTBK) prevented the production of pro-inflammatory mediators TNFα, IL-6, PGE 2 and nitrite from BV-2 microglia activated with LPS and IFNγ. These effects were accompanied by reduction in the levels of pro-inflammatory proteins COX-2 and iNOS. Involvement of NF-κB in the anti-inflammatory activity of OTBK was evaluated in experiments showing that the compound prevented phosphorylation, nuclear accumulation and DNA binding of p65 sub-unit induced by stimulation of BV-2 microglia with LPS and IFNγ. Exposure of mouse hippocampal HT22 neurons to conditioned media from LPS + IFNγ-stimulated BV-2 cells resulted in reduced cell viability and generation of cellular reactive oxygen species. Interestingly, conditioned media from LPS/IFNγ–stimulated BV-2 cells which were treated with OTBK did not induce neuronal damage or oxidative stress. OTBK was shown to increase protein levels of phospho-AMPKα, Nrf2 and HO-1 in BV-2 microglia. It was further revealed that OTBK treatment increased Nrf2 DNA binding in BV-2 microglia. The actions of the compound on AMPKα and Nrf2 were shown to contribute to its anti-inflammatory activity as demonstrated by diminished activity in the presence of the AMPK antagonist dorsomorphin and Nrf2 inhibitor trigonelline. These results suggest that OTBK inhibits neuroinflammation through mechanisms that may involve activation of AMPKα and Nrf2 in BV-2 microglia.

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