Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia

Wang, Zhi-Qiu; Wu, Du-Chu; Huang, Fei; Yang, Guo‐Yuan

doi:10.1016/j.brainres.2003.09.074

Cited by 132 publications

(88 citation statements)

References 34 publications

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“…at ASPET Journals on May 11, 2018 jpet.aspetjournals.org of middle cerebral artery occlusion may also reduce production of proinflammatory cytokine IL-1␤ mRNA and significantly decrease brain infarct volume (Wang et al, 2004b). As expected, a significant decrease of pERK1/2 levels was observed in the spinal cord sections obtained from SCI-operated mice that received PD98059.…”

Section: Pd98059 Treatment Reduces Injury Associated With Sci 111supporting

confidence: 77%

“…bolus of vehicle (saline) or 10 mg/kg PD98059 at 1 and 6 h (early treatment) or at 6 and 12 h (late treatment) after SCI or with U0126 (16 g/mouse) 30 min before and 1 and 6 h after SCI. The doses of PD98059 (10 mg/kg) used here were based on a previous in vivo study (Minutoli et al, 2005), and the dose of U0126 (16 g/mouse) was chosen in agreement with a previous study in vivo (Wang et al, 2004b). To investigate the motor score, in another set of experiments, the animals were treated with PD98059 at 1 and 6 h (early treatment) or at 6 and 12 h (late treatment) after SCI and daily until day 9 or with U0126 (16 g/mouse) 30 min before and 1 and 6 h after SCI and daily until day 9.…”

Section: Methodsmentioning

confidence: 99%

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Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

Genovese¹,

Esposito²,

Mazzon³

et al. 2008

J Pharmacol Exp Ther

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Mitogen-activated protein kinase (MAPK) signaling pathways involve two closely related MAPKs, known as extracellular signal-regulated kinase (ERK)1 and ERK2. The aim of the present study was to evaluate the contribution of MAPK3/MAPK1 in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), which is an inhibitor of MAPK3/MAPK1. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. PD98059 treatment (10 mg/kg i.p.) at 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-B activation, 6) phospho-ERK1/2 expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, PD98059 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that PD98059 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.Spinal cord injury (SCI) is a highly debilitating pathology (Maegele et al., 2005). Although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of limiting neuronal injury and promoting regeneration have been limited. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy. The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered and regenerated. Studies indicate that neurons continue to die for hours following traumatic SCI (Profyris et al., 2004). The events that characterize this successive phase to mechanical injury are called "secondary damage." Secondary damage is determined by a large number of cellular, molecular, and biochemical cascades. Considerable recent data suggest the presence of a local inflammatory response, which amplifies secondary damage.Moreover, various evidence has suggested that resident microglia and macrophages originating from blood are two key cell types related to the occurrence of neuronal degeneration in CNS after traumatic injury. In particular, when SCI occurs, microglia in parenchyma is activated, and macrophages in circulation can cross the blood-brain barrier to act as intrinsic spinal phagocytes. Therefore, these cells can release various neurotrophic peptides such as brain-derived neurotrophic factor (Batchelor et al., 2002), and laminin, which are excellent substrates for growing neuritis. Concomitantly, different proinflammatory mediators, ...

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Section: Pd98059 Treatment Reduces Injury Associated With Sci 111supporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

Genovese¹,

Esposito²,

Mazzon³

et al. 2008

J Pharmacol Exp Ther

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“…sion is associated with important neurological disorders, such as Alzheimer's disease [12,16]. Wang et al reported that inhibition of MEK/ERK1/2 pathway reduced proinflammation during cerebral ischemia [22]. Taken together, our findings might be a first study to demonstrate that 1) relationship of GJIC and p38 MAP kinase during neuronal stem cell differentiation, and 2) the role of GJIC via ERK1/2 in the neuronal stem cell-derived cells by treated with TPA.…”

Section: Discussionsupporting

confidence: 64%

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

Yang

Cho

Ahn

et al. 2005

The Journal of Veterinary Medical Science

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ABSTRACT. Gap junctional intercellular communications (GJIC) contributes to neural function in development and differentiation of CNS. In this study, we have investigated the expression of GJIC during the differentiation of neuronal stem cells and 12-Ø-tetradecanoylphorbol-13-acetate (TPA)-induced neuronal stem cell-derived cells from rat brain. During neuronal stem cell differentiation, expressions of Cx43 and 32 were increased for the duration of 72 hr, however the effect were decreased on the 7d. In the neuronal stem cell-derived cells, pretreatments with p38 MAP kinase inhibitor, SB203580, and MEK inhibitor, PD98059, could protect GJIC against TPA-induced inhibition of GJIC. Our data suggest that GJIC plays an important role during neuronal stem cell differentiation, and ERK1/2 and p38 MAP kinase signaling pathway may be closely related functionally to regulate gap junction in rat neuronal stem cell-derived cells. Neuronal stem cells are able to differentiate into astrocytes, neurons, and oligodendrocytes [3,10,23], when given the appropriate signals [2,7]. During the stage where the brain develops, gap junctional intercellular communication (GJIC) allows the diffusional exchange of ions and metabolites for communication between neighboring cells [8,14,20]. Connexin 32 and 43 were expressed in the neurons of adult rat or mouse [15,17], and Cx43 was the most abundant gap junction protein in the CNS [4,5]. However, no study has yet been performed to the role of gap junctions in rat neuronal stem cell differentiation. In the present study, we have examined protein expression of Cx43 and Cx32 during the neuronal stem cell differentiation and induction of Cx43 and Cx32. This can be elicited in neuronal stem cell-derived cells by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) and this induction showed that it can be prevented by the p38 MAP-Kinase inhibitor SB203580 and the MEK inhibitor PD98059. MATERIALS AND METHODSCell culture: Neuronal stem cells were prepared by culturing cells from cerebrum of embryonic day 17 (E17) Sprague-Dawley rat (Bio Genomics, Korea) fetus. Briefly, fresh cerebrums were dissociated in the presence of trypsin and DNase I and planted on a Petri dish (Nunc, IL). Cells were seeded at a density of 1~5 × 10 6 cells/ml in a mixture (1:1) of Dulbecco's modified Eagle's medium/Ham's F12 (DMEM/F12; Gibco) replenished with 2% B27 (Gibco), gentamycin (50 µg/ml), anti-PPLO (pleuro-pneumonia-like organism) reagent (100 µg/ml), recombinant human basic fibroblast growth factor (bFGF 20 ng/ml, Sigma), and epidermal growth factor (10 ng/ml).Scrape loading/ dye transfer (SL/DT) assay: Cells were treated with TPA for 1 hr. The GJIC assay was conducted at non-cytotoxic dose levels of the samples, as determined by the MTT assay. Following incubation, the cells were washed twice with 2 ml of PBS, Lucifer yellow was added to the washed cells and three scrapes were made with a surgical steel-bladed scalpel at low light intensities. These three scrapes were performed to ensure that the scrape travers...

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“…In a mouse model of stroke induced by transient occlusion of the middle cerebral artery, an increase in phosphorylated ERK in the nuclei of cortical cells was detected and pretreatment with PD98059 blocked ERK phosphorylation, resulting in a 55% decrease in focal infarct volume at 22 h and a 36% decrease at 72 h (Alessandrini et al, 1999). Using the same model, researchers confirmed these results using two additional MEK1 inhibitors U0126 and SL327 (Namura et al, 2001;Wang et al, 2003Wang et al, , 2004b. In a gerbil model of forebrain ischemia induced by bilateral carotid artery occlusion, Namura et al (2001) obtained similar results with MEK1 inhibitors.…”

Section: Erk Signaling Mediates Injury-induced Tissue Damage In Vivomentioning

confidence: 76%

A Death-Promoting Role for Extracellular Signal-Regulated Kinase

Zhuang

Schnellmann

2006

J Pharmacol Exp Ther

330

273

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Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated protein kinase superfamily, have been well characterized and are known to be involved in cell survival; however, recent evidence suggests that the activation of ERK1/2 also contributes to cell death in some cell types and organs under certain conditions. For example, ERK1/2 is activated in neuronal and renal epithelial cells upon exposure to oxidative stress and toxicants and deprivation of growth factors, and inhibition of the ERK pathway blocks apoptosis. ERK activation also occurs in animal models of ischemia-and trauma-induced brain injury and cisplatin-induced renal injury, and inactivation of ERK reduces the extent of tissue damage. In some studies, ERK has been implicated in apoptotic events upstream of mitochondrial cytochrome c release, whereas other studies have suggested the converse that ERK acts downstream of mitochondrial events and upstream of caspase-3 activation. ERK also can contribute to cell death through the suppression of the antiapoptotic signaling molecule Akt. Here we summarize the evidence and mechanism of ERK-induced apoptosis in both cell culture and in animal models.

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Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia

Cited by 132 publications

References 34 publications

Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

A Death-Promoting Role for Extracellular Signal-Regulated Kinase

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