The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

Krementsov, Dimitry N.; Thornton, Tina M.; Teuscher, Cory; Rincón, Mercedes

doi:10.1128/mcb.00688-13

Cited by 98 publications

(72 citation statements)

References 74 publications

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“…Generation and amplification of TNF-a and IL-1b have been reported to be regulated by NF-jB p65 [26][27][28]. In addition to NF-jB p65 signaling, MAPKs are also important signaling molecules involved in the production of pro-inflammatory mediators and cytokines and the modulation of NF-jB p65 in microglia [29,30]. One of the MAPK families, p38, is related to LPS signaling in microglial cells, which respond to pro-inflammatory cytokines [31,32].…”

Section: Discussionmentioning

confidence: 99%

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

et al. 2015

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Microglia is the resident innate immune cells that sense pathogens and tissue injury in the central nervous system. Microglia becomes activated in response to injury, infection, and other stimuli that threaten neuronal survival. Microglia activation plays an important role in neurodegenerative diseases. Neochlorogenic acid (NCA) is a natural polyphenolic compound found in dried fruits and other plants. Although previous studies have shown that phenolic acids including NCA have outstanding antioxidant, antibacterial, antiviral, and antipyretic activities, there has not yet been investigated for anti-inflammatory effects. Therefore, for the first time we have examined the potential of NCA to inhibit microglial activation and pro-inflammatory responses in the brain. We found that lipopolysaccharide-induced inducible nitric oxide synthase, and cyclooxygenase-2 expression, and nitric oxide formation was suppressed by NCA in a dose-dependent manner in BV2 microglia. NCA also inhibited the production of pro-inflammatory mediators, tumor necrosis factor-α and interleukin-1 beta. Furthermore, phosphorylated nuclear factor-kappa B p65 and p38 mitogen-activated protein kinase activation were blocked by NCA. Taken together, these results suggest that NCA exerts neuroprotective effects through the inhibition of pro-inflammatory pathways in activated microglia.

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Section: Discussionmentioning

confidence: 99%

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

et al. 2015

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“…P38 MAPK (p38) is a member of the MAPK family and is centrally involved in diverse cellular processes, including inflammation, cell differentiation, cell growth and cell death 19. A wealth of data has indicated that p38 is also a key regulator in multiple renal diseases 20.…”

Section: Introductionmentioning

confidence: 99%

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Fan

Zhen

et al. 2016

J Cellular Molecular Medi

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Focal adhesion kinase (FAK) is a non‐receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet‐induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder‐related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c‐Src, Rho GTPase and mitogen‐activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low‐density lipoprotein (ox‐LDL) triggered hyper‐phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re‐arrangement of F‐actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre‐treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper‐activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox‐LDL damaged podocytes in a FAK/p38‐dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia‐related podocyte damage and proteinuria.

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Section: Introductionmentioning

confidence: 99%

“…NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production of pro-inflammatory mediators generated during neuroinflammation can damage neighbouring neurons, and further activate the microglia, as well as other glia cells resulting in a self-perpetuating cycle [2,4,9].Furthermore, activation of the microglia and the resulting neuroinflammation play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) [10]. Consequently, pharmacological modulation of pro-inflammatory mediators generated by the microglia during chronic inflammation and modulation of the signalling pathways responsible for their production is an important target in treating severe neuroinflammatory disorders.…”

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confidence: 99%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40µM) for 24 hours. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, PGE2, iNOS, COX-2 and mPGES-1. BACE-1 activity and Aβ levels were measured with ELISA kits. Protein levels of targets in NF-κB and p38 MAPK signalling, as well as HO-1, NQO1 and Nrf2 were also measured with western blot. NF-κB binding to the DNA was investigated using EMSA. MTT, DNA fragmentation and ROS assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, TNFα, and IL-6), Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti-inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders. 3 KeywordsArtemether, neuroinflammation, BV2 microglia, HT22 hippocampal neurons, NF-κB, Nrf2 4 BackgroundIn the central nervous system (CNS), the microglia plays an important role in immune defence and tissue repair [1]. Under normal conditions, these cells provide surveillance whilst maintaining homeostasis in the brain [2]. In response to injury, harmful toxins, infection or inflammation, microglial cells become activated, secreting pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species and pro-inflammatory cytokines including IL-6 and TNFα [3,4]. These pro-inflammatory mediators are mainly regulated by the transcription factor NF-κB [5]. NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production o...

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The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

Cited by 98 publications

References 74 publications

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

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