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

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, PGE2 and nitrite from BV-2 microglia activated with LPS and IFN. These effects were accompanied by a reduction in the levels of pro-inflammatory proteins COX-2 and iNOS. Involvement of NF-B 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 IFN. Exposure of mouse hippocampal HT22 neurons to conditioned media from LPS + IFN-stimulated BV-2 cells resulted in reduced cell viability and generation of cellular reactive oxygen species. Interestingly, conditioned media from LPS/IFN-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.

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke

“…Neuroinflammation can arise from an imbalance between proinflammatory and anti-inflammatory phenotypes favoring the former, with a reversal in the balance ameliorating disease progression, including stroke [44]. The presence of IRF5, IRF8, P2X4R, P2X7R, and P2Y12R promotes microglia polarization towards proinflammatory phenotypes, while CD163, CD206, arginase 1, Ym-1, Nrf2, Sirt1, and Heme Oxygenase-1 (HO-1) shift microglia to anti-inflammatory phenotypes [27,[45][46][47][48]. We found that cerebral ischemia-associated neuroinflammation was accompanied by the activation of microglia and astrocytes, along with the reduction of neurons and compromise of the blood-brain barrier tight junction.…”

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

“…Microglia, in the alternative activation polarization, release Transforming Growth Factor (TGF-β), IL-4, and IL-10, with the consequences of suppressing inflammation and restoring homeostasis. The presence of P2X4R, P2X7R, and P2Y12R promote microglia polarization towards the classical activation state, while CD163 and arginase 1 promote polarizing microglia towards the alternative activation state [32,[38][39][40][41][42]. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains.…”

“…As with macrophages, microglia adopt a series of molecular and biochemical events to switch genetic programs, morphological cytoskeletons, cell membrane surface presentation, and functional outcomes. The rising of pro-inflammatory and the subsiding of anti-inflammatory phenotypes of microglia have been implicated in various neurodegenerative diseases as well as a reversal in the balance of ameliorate disease progression [38][39][40][41]. Typically, neurotoxic cytokines such as TNF-α, IL-1β, IL-18, IL-6, IFN-γ, NO, PGE2, and free radicals come from classical activation polarized microglia.…”

The Pharmacological Action of Kaempferol in Central Nervous System Diseases: A Review

“…Also, tiliroside prevented the phosphorylation of p65 subunit of NF-kB, which is one of the critical steps in the microglia NF-kB activation pathway, after stimulation of BV-2 microglia with LPS and IFNγ. The mouse hippocampal HT22 neuron cell line in medium containing LPS + BV-2 stimulated by IFNγ resulted in reduced cell viability and generation of reactive species of oxygen, when these cells were exposed to tiliroside, indicating no damage to neural cells or generation of oxidative stress, besides having promoted the activity of the AMPK and Nrf2/HO-1 pathways responsible for suppressing neuroinflammation ( Velagapudi et al, 2019 ).…”