Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα

Xing, Bin; Bachstetter, Adam D.; Eldik, Linda J. Van

doi:10.1186/1750-1326-6-84

Cited by 82 publications

(89 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have demonstrated that several mechanisms are involved in the pathogenicity of LPS that involve the JNK and P38-MAPK pathways in the production of inflammatory mediators (Xing et al 2011;Wang et al 2012). In the current study, we investigated the neuroprotective activity of an anti-inflammatory compound lupeol against LPS-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, it has been determined that pharmacological inhibition of p38α-MAPK decreased the levels of the inflammatory cytokines TNF-α and IL-1β, and protected neuronal cells from synaptic protein loss and neurite degeneration (Xing et al 2011;Munoz et al 2007). The JNK signaling cascade acts on AP-1 to promote neuroinflammation and neurodegeneration or interferes with cell deathassociated proteins such as the BCL-2 family of proteins to activate the mitochondrial apoptotic pathway (Bendottil et al 2006;Putcha et al 2003;Tournier et al 2000).…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Badshah

Ali

Rehman

et al. 2015

J Neuroimmune Pharmacol

102

View full text Add to dashboard Cite

Recent studies have demonstrated a close interaction between neuroinflammatory responses, increased production of inflammatory mediators, and neurodegeneration. Pathological findings in neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease have shown common signs of neuroinflammation and neurodegeneration. Lupeol, a natural pentacyclic triterpene, has revealed a number of pharmacological properties including an anti-inflammatory activity. This study aimed to evaluate the effect of lupeol against lipopolysaccharide (LPS)-induced neuroinflammation in the cortex and hippocampus of adult mice. Our results showed that systemic administration of LPS induced glial cell production of proinflammatory cytokines, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1β, while co-treatment with lupeol significantly inhibited the LPS-induced activation of microglia and astrocytes, and decreased the LPS-induced generation of TNF-α, iNOS, and IL-1β. The intracellular mechanism involved in the LPS-induced activation of inflammatory responses includes phosphorylation of P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which was significantly inhibited by lupeol. We further elucidated that lupeol inhibited the LPS-induced activation of the mitochondrial apoptotic pathway and reversed the LPS-induced expression of apoptotic markers such as Bax, cytochrome C, caspase-9, and caspase-3. Taken together; our results suggest that lupeol inhibits LPS-induced microglial neuroinflammation via the P38-MAPK and JNK pathways and has therapeutic potential to treat various neuroinflammatory disorders.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Badshah

Ali

Rehman

et al. 2015

J Neuroimmune Pharmacol

102

View full text Add to dashboard Cite

show abstract

“…Increased glutamate transmission (and associated excitotoxicity) is thought to play a role in the inflammation-driven neurodegenerative process of MS. In the model system used by Nistico et al, IL-1β secreted by activated microglia was found to suppress GABAergic inhibitory transmission, with limited effects on glutaminergic transmission - in contrast to the impaired hippocampal glutamatergic transmission observed in another EAE model (Xing et al, 2011). However, in both cases the normal balance between excitation and inhibitory inhibition was disrupted, subverting normal synaptic function.…”

Section: Potential Mechanismsmentioning

confidence: 95%

Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity

2015

View full text Add to dashboard Cite

Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain’s resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro-inflammatory cytokines (e.g. interleukin-1beta or IL-1β) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1β is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1β on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain-derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by caused by infection or injury, and it plays a critical role in many of the same hippocampal plasticity and memory processes compromised by dysregulated production of IL-1β. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses.

show abstract

“…MAPK rescued neurons and reduces synaptic protein loss by suppressing LPSinduced TNFα production [30]. Consequently, pharmacological modulation of p38MAPK signalling following LPS stimulation of the microglia is an important strategy in preventing neurodegeneration.…”

Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 99%

“…The p38MAPK signalling has been shown to be critical in the expression and activity of pro-inflammatory cytokines in the CNS [30]. In addition, p38 is involved in regulating the production of crucial inflammatory mediators such as COX-2 in macrophages [31].…”

Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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...

show abstract

Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα

Cited by 82 publications

References 51 publications

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Protective Effect of Lupeol Against Lipopolysaccharide-Induced Neuroinflammation via the p38/c-Jun N-Terminal Kinase Pathway in the Adult Mouse Brain

Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity

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

Contact Info

Product

Resources

About