Anti-Neuroinflammatory Effects of Fucoxanthin via Inhibition of Akt/NF-κB and MAPKs/AP-1 Pathways and Activation of PKA/CREB Pathway in Lipopolysaccharide-Activated BV-2 Microglial Cells

Zhao, Dong; Kwon, Seung-Hwan; Chun, Yoon S.; Gu, Ming-Yao; Yang, Hyun Ok

doi:10.1007/s11064-016-2123-6

Cited by 86 publications

(68 citation statements)

References 33 publications

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“…For instance, AKT negatively regulates LPS-induced TNF-α and IL-6 levels in the bone marrow macrophages [ 37 ]. Phosphorylated AKT also promotes the expression of inflammatory molecules, including iNOS and COX-2 [ 38 ]. As shown by Saponaro et al, LPS binds to TLR4 and activates AKT signaling to alter the production of the proinflammatory cytokine iNOS in microglial cells [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Nam

Yoon

et al. 2018

J Neuroinflammation

137

111

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BackgroundThe FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined.MethodsBV2 microglial cells were treated with ibrutinib (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry.ResultsIbrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1β proinflammatory cytokine levels.ConclusionsOur data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1308-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Nam

Yoon

et al. 2018

J Neuroinflammation

137

111

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“…Other groups of bioactive compounds, normally present in foods, especially in the Mediterranean diet, such as phenolic compounds, phytosterols and carotenoids (e.g., lycopene, fucoxanthin, and lutein) exhibit anti‐inflammatory properties on microglia (Pena‐Altamira et al, ; Jeong et al, ; Sachdeva & Chopra, ; D. Zhao, Kwon, Chun, Gu, & Yang, ), but the mechanisms underlined their effects still remain to be defined.…”

Section: Alimentary Components Driving Pro‐regenerative Microglia Funmentioning

confidence: 99%

How to reprogram microglia toward beneficial functions

Fumagalli

Lombardi

Gressèns

et al. 2018

Glia

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Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.

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“…For example, fucoxanthin, a carotenoid abundant in brown seaweeds, exerted anti-inflammatory effects and reduced reactive oxygen species levels in Aβ42 treated BV2 microglial cells (Pangestuti et al, 2013). Moreover, in another in vitro inflammation-induced microglial cell culture study, fucoxanthin was able to inhibit the secretion of inflammatory cytokines after LPS treatment (Zhao et al, 2017). However, no in vivo data on the anti-inflammatory effect of fucoxanthin are currently available.…”

Section: Nutritional Approaches Towards Immunomodulation and Their Pomentioning

confidence: 99%

Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer’s Disease

Peña-Altamira

Petralla

Massenzio

et al. 2017

Front. Aging Neurosci.

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The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, depending on brain microenvironment, has completely changed the understanding of microglia in brain aging and neurodegenerative diseases. Microglia polarization is particularly important in aging since an increased inflammatory status of body compartments, including the brain, has been reported in elderly people. In addition, inflammatory markers, mainly derived from activated microglia, are widely present in neurodegenerative diseases. Microglial inflammatory dysfunction, also linked to microglial senescence, has been extensively demonstrated and associated with cognitive impairment in neuropathological conditions related to aging. In fact, microglia polarization is known to influence cognitive function and has therefore become a main player in neurodegenerative diseases leading to dementia. As the life span of human beings increases, so does the prevalence of cognitive dysfunction. Thus, therapeutic strategies aimed to modify microglia polarization are currently being developed. Pharmacological approaches able to shift microglia from M1 pro-inflammatory to M2 neuroprotective phenotype are actually being studied, by acting on many different molecular targets, such as glycogen synthase kinase-3 (GSK3) β, AMP-activated protein kinase (AMPK), histone deacetylases (HDACs), etc. Furthermore, nutritional approaches can also modify microglia polarization and, consequently, impact cognitive function. Several bioactive compounds normally present in foods, such as polyphenols, can have anti-inflammatory effects on microglia. Both pharmacological and nutritional approaches seem to be promising, but still need further development. Here we review recent data on these approaches and propose that their combination could have a synergistic effect to counteract cognitive aging impairment and Alzheimer’s disease (AD) through immunomodulation of microglia polarization, i.e., by driving the shift of activated microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype.

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Anti-Neuroinflammatory Effects of Fucoxanthin via Inhibition of Akt/NF-κB and MAPKs/AP-1 Pathways and Activation of PKA/CREB Pathway in Lipopolysaccharide-Activated BV-2 Microglial Cells

Cited by 86 publications

References 33 publications

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice

How to reprogram microglia toward beneficial functions

Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer’s Disease

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