Abstract
Increasing evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play a key role in neurodegeneration. Fisetin, a plant flavonol commonly found in fruits and vegetables, is frequently added to nutritional supplements due to its antioxidant properties. In the present study, treatment with fisetin inhibited microglial cell migration and ROS (reactive oxygen species) production. Treatment with fisetin also effectively inhibited LPS plus IFN-γ-induced nitric oxide (NO) production, and inducible nitric oxide synthase (iNOS) expression in microglial cells. Furthermore, fisetin also reduced expressions of iNOS and NO by stimulation of peptidoglycan, the major component of the Gram-positive bacterium cell wall. Fisetin also inhibited the enhancement of LPS/IFN-γ- or peptidoglycan-induced inflammatory mediator IL (interlukin)-1 β expression. Besides the antioxidative and anti-inflammatory effects of fisetin, our study also elucidates the manner in fisetin-induced an endogenous anti-oxidative enzyme HO (heme oxygenase)-1 expression. Moreover, the regulatory molecular mechanism of fisetin-induced HO-1 expression operates through the PI-3 kinase/AKT and p38 signaling pathways in microglia. Notably, fisetin also significantly attenuated inflammation-related microglial activation and coordination deficit in mice in vivo. These findings suggest that fisetin may be a candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.
Highlights
Microglial activation leads to neuroinflammatory responses that exert both beneficial and detrimental effects, including host defense and tissue repair processes [1,2]
We used BV-2 microglia to study the effects of fisetin on neuroinflammatory responses
Since Heme oxygenase (HO)-1 induction is known to participate in regulation of inflammatory responses, we investigated whether fisetin might lead to HO-1 induction
Summary
Microglial activation leads to neuroinflammatory responses that exert both beneficial and detrimental effects, including host defense and tissue repair processes [1,2]. Fisetin (3,3',4',7-tetrahydroxyflavone; Figure 1A), a high Trolox-equivalent antioxidant, is found in strawberry, persimmon, grape and cucumber [21] Due to it being a hydrophobic compound, fisetin penetrates cell membranes accumulating in cells to exert its antioxidative effects [22], with wide-ranging biological activities including antiaging, anti-inflammatory, neuroprotection and anticancer effects [23,24]. We have reported that neuroinflammatory responses can be repressed by HO-1 induction in microglia [34,35] and astrocytes [36], and that increased HO-1 expression protects neurons against neurotoxin-induced cell death [37,38]. We addressed whether, in addition to inhibiting cytokine production, HO-1 expression contributes to fisetin-regulated anti-inflammatory responses in microglial cells
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