Abstract
In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when constantly activated, this process can become detrimental through the release of neurotoxic factors that amplify underlying disease. In consequence, this study presents the anti-inflammatory and immunomodulatory properties of o-orsellinaldehyde, a natural compound found by an in silico approach in the Grifola frondosa mushroom, in astrocytes and microglia cells. For this purpose, primary microglia and astrocytes were isolated from mice brain and cultured in vitro. Subsequently, cells were exposed to LPS in the absence or presence of increasing concentrations of this natural compound. Specifically, the results shown that o-orsellinaldehyde strongly inhibits the LPS-induced inflammatory response in astrocytes and microglia by decreasing nitrite formation and downregulating iNOS and HO-1 expression. Furthermore, in microglia cells o-orsellinaldehyde inhibits NF-κB activation; and potently counteracts LPS-mediated p38 kinase and JNK phosphorylation (MAPK). In this regard, o-orsellinaldehyde treatment also induces a significant cell immunomodulation by repolarizing microglia toward the M2 anti-inflammatory phenotype. Altogether, these results could partially explain the reported beneficial effects of G. frondosa extracts on inflammatory conditions.
Highlights
The participation of the inflammatory process is being increasingly recognized to play detrimental roles in diverse neurological conditions and pathologies including primary degenerative disorders such as Parkinson’s and Alzheimer’s diseases and primary inflammatory diseases such as multiple sclerosis and HIV dementia, as well as in brain injuries as consequence of trauma and stroke [1,2]
Astrocyte and microglia pretreatment with o-orsellinaldehyde reduced the over-expression of HO-1 caused by the LPS stimulation that could be detrimental for the cells. These results show that the G. frondosa- derived natural compound is able to relieve the LPS-stimulated HO-1 expression, which has been described to be mediated by Nrf2 and AREs [31]
In order to validate that o-orsellinaldehyde inhibits IKβα phosphorylation in a neurological context, we examined the NFkB signaling pathway in response to LPS in primary microglial cells
Summary
The participation of the inflammatory process is being increasingly recognized to play detrimental roles in diverse neurological conditions and pathologies including primary degenerative disorders such as Parkinson’s and Alzheimer’s diseases and primary inflammatory diseases such as multiple sclerosis and HIV dementia, as well as in brain injuries as consequence of trauma and stroke [1,2] Such an inflammation reaction is favorized by the activity of supporting glial cells such as astrocytes and microglia that surrounds the neurons [3]. The long-term or excessive activation of these cells is directly correlated with chronic neuroinflammation which will become detrimental due to the overproduction of neurotoxins and cytokines, that could promote a cascade of events that will culminate in a progressive neuronal death [7,8] In this activation process microglial cells adopt diverse functional phenotypes that range from the alternative anti-inflammatory M2 phenotype, to the classic pro-inflammatory and neurotoxic phenotype, known as M1 [9,10]
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