Downregulation of Matrix Metalloproteinase-9 and Attenuation of Edema via Inhibition of ERK Mitogen Activated Protein Kinase in Traumatic Brain Injury

Mori, Tatsuro; Wang, Xiaoying; Aoki, Toshiaki; Lo, Eng H.

doi:10.1089/089771502320914642

Cited by 117 publications

(73 citation statements)

References 54 publications

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“…Inhibition of ERK1͞2 can reduce neuronal death in several settings known to cause extensive PARP-1 activation (17,19,31). Here we show that ERK1͞2 activation is required both for PARP-1 activation and for PARP-1-induced neuron and astrocyte death.…”

Section: Discussionmentioning

confidence: 56%

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Kauppinen¹,

Chan²,

Suh³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

178

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Sustained activation of poly(ADP-ribose) polymerase-1 (PARP-1) and extracellular signal-regulated kinases 1͞2 (ERK1͞2) both promote neuronal death. Here we identify a direct link between these two cell death pathways. In a rat model of hypoglycemic brain injury, neuronal PARP-1 activation and subsequent neuronal death were blocked by the ERK1͞2 inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059). In neuron cultures, PARP-1-mediated neuronal death induced by N-methyl-Daspartate, peroxynitrite, or DNA alkylation was similarly blocked by ERK1͞2 pathway inhibitors. These inhibitors also blocked PARP-1 activation and PARP-1-mediated death in astrocytes. siRNA down-regulation of ERK2 expression in astrocytes also blocked PARP-1 activation and cell death. Direct effects of ERK1͞2 on PARP-1 were evaluated by using isolated recombinant enzymes. The activity of recombinant human PARP-1 was reduced by incubation with alkaline phosphatase and restored by incubation with active ERK1 or ERK2. Putative ERK1͞2 phosphorylation sites on PARP-1 were identified by mass spectrometry. Using site-directed mutagenesis, these sites were replaced with alanine (S372A and T373A) to block phosphorylation, or with glutamate (S372E and T373E) to mimic constitutive phosphorylation. Transfection of PARP-1 deficient mouse embryonic fibroblasts with the mutant PARP-1 species showed that the S372A and T373A mutations impaired PARP-1 activation, whereas the S372E and T373E mutations increased PARP-1 activity and eliminated the effect of ERK1͞2 inhibitors on PARP-1 activation. These results suggest that PARP1 phosphorylation by ERK1͞2 is required for maximal PARP-1 activation after DNA damage.DNA damage ͉ hypoglycemia ͉ mitogen-activated protein kinase ͉ astrocyte ͉ neuron P oly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated by DNA strand breaks and functionally linked to DNA repair (1). PARP-1 activation in neurons occurs in ischemia, trauma, hypoglycemia, excitotoxicity, multiple sclerosis, and other conditions involving oxidative stress or inflammation (2-5). When activated, PARP-1 consumes NAD to form poly(ADP-ribose) (PAR) on specific acceptor proteins. The poly(ADP-ribosyl)ation modifies protein binding to DNA and other proteins to facilitate DNA repair and prevent chromatid exchange (1, 6). However, extensive activation of PARP-1 leads to NAD depletion and cell death (7-9). PARP inhibitors and PARP-1 gene deletion can markedly improve neuronal survival in ischemia and other disorders (10-12). PARP-1 also interacts with several transcription factors (13), and the coactivation of nuclear factor B (NF-B) by PARP-1 promotes the cellular inflammatory response (14-16).Like PARP-1, the extracellular signal-regulated kinases 1 and 2 (ERK1͞2) are activated by ischemia and other conditions that generate oxidative stress (17-22). ERK1͞2, p38, and c-Jun-Nterminal kinase (JNK) comprise the major subgroups of the mitogen-activated protein kinases (MAPKs) (23), which are serine͞ threonine kinases involved...

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Section: Discussionmentioning

confidence: 56%

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Kauppinen¹,

Chan²,

Suh³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

178

View full text Add to dashboard Cite

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“…Contrasting effects have also been described for ERK. Whereas ERK activation prevented apoptosis after growth factor withdrawal in cerebellar neurons and PC12 cells, 18 our laboratory 13,24,25 and others 26,27 have shown that ERK inhibition protected against cortical neuronal injury. Overall, the literature suggests that contributions of individual MAP kinases depend on the cell types and the nature and severity of the insult involved.…”

Section: Discussionmentioning

confidence: 82%

Interactions Between p38 Mitogen-Activated Protein Kinase and Caspase-3 in Cerebral Endothelial Cell Death After Hypoxia-Reoxygenation

Lee

2003

Stroke

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Background and Purpose-The emerging concept of the neurovascular unit in stroke reemphasizes the need to focus on endothelial responses in brain. In this study we examined the role of mitogen-activated protein (MAP) kinase signaling in the regulation of hypoxic cell death in cerebral endothelial cells. Methods-Human cerebral microvascular endothelial cells were exposed to 4 to 12 hours of hypoxia followed by 12 to 24 hours of reoxygenation. Cytotoxicity was measured by quantifying lactate dehydrogenase release. DNA laddering and caspase-3 activity were assessed to document a role for caspase-dependent cell death. zVAD-fmk and zDEVD-fmk were used to inhibit caspases. Activation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) was assessed with Western blotting and kinase activity assays. U0126, SB203580, and SP600125 were used to interrupt the ERK, p38, and JNK pathways, respectively. Results-Endothelial cell death occurred primarily during reoxygenation. DNA laddering and caspase activation were observed, and cytotoxicity was ameliorated by caspase inhibitors (20 mol/L of zVAD-fmk or zDEVD-fmk). Among the 3 major MAP kinases, only p38 was transiently activated during reoxygenation, and inhibition with 10 mol/L of SB203580 significantly reduced cytotoxicity. No effects were observed with other MAP kinase inhibitors. Cytoprotection with SB203580 was not accompanied by caspase downregulation. In contrast, cytoprotection with zVAD-fmk was associated with a decrease in p38 activation. Furthermore, cleavage of MEKK1 (an upstream kinase of p38) was significantly reduced by zVAD-fmk. Conclusions-Cerebral

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“…MAP kinase signaling pathways are known to play key roles in cytoplasmic-nuclear signaling transmission in response to various extracellular stimuli, resulting in the production of cytokines, tissue damage, and cell death (21,25). In primary cultured hepatocytes, hyposmotic stress activates ERK1/2 and p38 phosphorylation (20).…”

Section: Discussionmentioning

confidence: 99%

Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats

Ling

Smith²,

Kie³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats. Am J Physiol Regul Integr Comp Physiol 287: R801-R808, 2004; 10.1152/ajpregu.00715.2003.-This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum ␣1-acid glycoprotein (AG), TNF-␣ (TNF), and IL-1␤ (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.

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Downregulation of Matrix Metalloproteinase-9 and Attenuation of Edema via Inhibition of ERK Mitogen Activated Protein Kinase in Traumatic Brain Injury

Cited by 117 publications

References 54 publications

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2

Interactions Between p38 Mitogen-Activated Protein Kinase and Caspase-3 in Cerebral Endothelial Cell Death After Hypoxia-Reoxygenation

Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats

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