Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species

Liu, Hongtao; Du, Yifeng; He, Junlin; Chen, Wenjuan; Li, Wenming; Yang, Zhu; Wang, Yingxiong; Yu, Chao

doi:10.1016/j.jep.2010.03.037

Cited by 59 publications

(34 citation statements)

References 52 publications

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“…Deviation from the fine tuning of MAPK signaling pathways has been implicated in the development of many neurodegenerative diseases such as AD, PD, and amyotrophic lateral sclerosis (ALS). Hyper phosphorylation of MAPK molecules ultimately activates the transcription factor NF-κB and subsequent production of inflammatory molecules (26,71). Therefore, in addition to our data showing that CD-101 regulates LPS-induced NF-κB activation, we further evaluated the effect of CD-101 on the upstream p38MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 98%

Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

Park

Kim

et al. 2013

J Pharmacol Sci

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Abstract. Microglial-mediated neuroinflammation has recently been implicated as one of the important mechanisms responsible for the progression of neurodegenerative diseases. Activated microglia cells produce various neurotoxic factors that are harmful to neurons. Therefore, suppression of the inflammatory response elicited by activated microglia is considered a potential therapeutic target for neurodegenerative diseases. The cannabinoid (CB) system is widespread in the central nervous system and is very crucial for modulating a spectrum of neurophysiological functions such as pain, appetite, and cognition. In the present study, we synthesized and investigated a novel CB derivative (CD-101) for its ability to suppress lipopolysaccharide (LPS)-mediated activation of BV-2 microglial cells and subsequent release of various inflammatory mediators. CD-101 significantly inhibited the production of inflammatory markers such as nitric oxide, cyclooxygenase-2, and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. The anti-neuroinflammatory effect of this novel cannabinoid derivative occurred by inhibiting p38MAPK phosphorylation and by decreasing nuclear translocation of p65 subunit of nuclear factor kappa-B in LPS-stimulated BV-2 microglial cells. These results suggest that the use of the cannabinoid derivative CD-101 might be a potential therapeutic target against neuroinflammatory disorders.

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Section: Discussionmentioning

confidence: 98%

Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

Park

Kim

et al. 2013

J Pharmacol Sci

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“…[44][45][46] Recent studies have also shown that LPS stimulates NF-jB activation by both phosphorylating and degrading IjB following activation of IKK and phosphorylation of MAPKs and PI3K/Akt. [47][48][49] Moreover, inhibition of the phosphorylation of MAPKs and PI3K/Akt also contributes to the inhibition of iNOS and COX-2 expression as well as inhibition of gene expression of cytokines and chemokines in microglial cells.…”

Section: Discussionmentioning

confidence: 99%

Lonicera japonicaTHUNB. Extract Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses by Suppressing NF-κB Signaling in BV-2 Microglial Cells

Kwon

Hong

et al. 2015

Journal of Medicinal Food

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In the current study, we evaluated the anti-inflammatory effects of Lonicera japonica THUNB. (LJ) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Our results indicated that LJ significantly inhibits LPS-stimulated production of nitric oxide (NO) and prostaglandin E2 (PGE2). In addition, LJ inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the protein and mRNA levels. In LPSstimulated BV-2 microglial cells, LJ inhibited proinflammatory cytokines and chemokines, tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) enzymatic activities, and/or mRNA expression, as well as reactive oxygen species (ROS) production. LJ significantly suppressed activation of nuclear factor-jB (NF-jB) and its translocation from the cytosol to the nucleus and suppressed the DNA-binding activity of NF-jB. Furthermore, LJ significantly inhibited phosphorylation of c-Jun N-terminal kinase ( JNK), extracellular signalregulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinases (PI3K)/Akt, and Janus kinase 1 ( JAK1)/signal transducer and activator of transcription (STAT)1/3. Collectively, our findings indicated that the antineuroinflammatory properties of LJ in LPS-induced BV-2 microglial cells is due to downregulation of proinflammatory cytokines and chemokines downstream of inhibition of NF-jB activation.

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“…In our previous study, the increase of MAPKs was detected after 15 min of LPS stimulation, reached a maximum after 30 min, and then decreased. It was shown that the activation of MAPKs is before the activation of NF-κB (26). These data demonstrated that puerarin down-regulates NF-κB through suppression of MAPKs phosphorylation.…”

Section: Puerarin Represses Phosphorylation Of Some Of Mapks In N9 Cementioning

confidence: 72%

Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-κB translocation

Zheng

Yu²,

Yang

2012

Int J Oncol

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Abstract. Microglial cells play a critical role in mediating central nervous system inflammatory processes. Activated microglial cells induced by proinflammatory factor, such as lipopolysaccharide (LPS), release many kinds of neurotoxic cytokines including reactive oxygen species (ROS) which contributes to the pathogenesis of neurodegenerative diseases. Puerarin, extracted from kudzu root, possesses the characteristic of neuroprotection, antioxidation and anticancer. In the present study, we observed that LPS induced over-production of nitric oxide (NO) and increased the level of intracellular ROS in N9 microglial cells, but it was inhibited by puerarin. Furthermore, treatment with puerarin on N9 cells suppressed the over-expression of inducible nitric oxide synthase (iNOS) induced by LPS which is implicated in intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) level, phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathway. We also observed that the enhanced phosphorylation of p38, JNK and ERK1/2 in N9 cells induced by LPS were inhibited by puerarin, otherwise the down-regulation of O-GlcNAcylation level of protein in N9 cell induced by LPS was up-regulated by pretreatment with puerarin. These results indicate that puerarin effectively inhibits microglia activation induced by LPS through inhibiting expression of iNOS, production of NO and ROS which was mediated via regulating O-GlcNAcylation, phosphorylation of MAPK and NF-κB translocation. IntroductionMicroglial cells, macrophage-like cells in the central nervous system, participate in CNS immune response through releasing a variety of factors, including trophic factors and chemokines, to promote neuroprotection (1). Whereas under chronic inflammatory environment, excessive activation of microglia cells secrete cytotoxic substances and neurotoxic cytokines, such as reactive oxygen species (ROS) and nitric oxide (NO) which contribute to the pathogenesis of neurodegenerative diseases (2). Lipopolysaccharide (LPS), which consist in outer membrane of gram-negative bacteria as potent pro-inflammatory agents, induce microglial cell inflammatory injury through releasing proinflammatory mediators such as NO generated by inducible nitric oxide synthase (iNOS) (3,4). NO is considered as a main risk factor of progressive damage in neurodegenerative diseases (5,6). Microglia cell inflammatory response to LPS is involved in speedy regulation of many signal transduction molecules. The regulation of a signal pathway, such as mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB), is implicated in major molecular mechanisms of LPS-induced NO and ROS production in microglial cells (4,(6)(7)(8).O-Linked O-GlcNAcylation of protein, a single monosaccharide N-acetylglucosamine (GlcNAc) attached to the hydroxyl groups of specific serine or threonine residues, is an important post-translational modification on nuclear and cytoplasmic proteins (9,10). More than 500 proteins have been identified to be O-GlcNAcylated...

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Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species

Cited by 59 publications

References 52 publications

Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

Lonicera japonicaTHUNB. Extract Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses by Suppressing NF-κB Signaling in BV-2 Microglial Cells

Puerarin suppresses production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through regulating MAPK phosphorylation, O-GlcNAcylation and NF-κB translocation

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