The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Downregulation of Matrix Metalloproteinase-9 and Attenuation of Edema via Inhibition of ERK Mitogen Activated Protein Kinase in Traumatic Brain Injury
Abstract
Emerging data suggest that matrix metalloproteinase-9 (MMP-9) plays a critical role in the pathophysiology of brain injury. However, the regulatory mechanisms involved in vivo remain unclear. In this study, we focus on a mitogen activated protein kinase (MAPK) pathway that may trigger MMP-9 after traumatic brain injury. We aim to show that inhibition of the extracellular signal regulated kinase (ERK) would attenuate MMP-9 levels, reduce blood-brain barrier damage, and attenuate edema after trauma induced by controlled cortical impact in mouse brain. Western blots showed that phospho-ERK was rapidly upregulated after trauma. Treatment with U0126, which inhibits MEK, the kinase upstream of ERK, effectively prevented the activation of ERK. After trauma, gelatin zymography showed an increase in MMP-9. U0126 significantly reduced trauma-induced MMP-9 levels. Correspondingly, U0126 ameliorated the degradation of the tight junction protein ZO-1, which is an MMP-9 substrate, and significantly attenuated tissue edema. At 7 days after trauma, traumatic lesion volumes were significantly reduced by U0126 compared with saline-treated controls. These data indicate that the ERK MAPK pathway triggers the upregulation in MMP-9 after trauma, and further suggest that targeting the upstream signaling mechanisms that regulate deleterious MMP-9 activity may reveal new therapeutic opportunities for traumatic brain injury.
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“Activation of ERK1/2 results in increased ZO-1 degradation during traumatic brain injury (51), decreased ZO-1 and claudin 5 expression in brain endothelium during HIV infection (52,53), and reduced occludin and claudin 5 expression in BBB endothelium during ischemic stroke (54).”
From Bacterial induction of Snail1 contributes to blood-brain barrier disruption (2015) · cites this paper as [51]
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Cites
Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis
Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., & Greenberg, M. E. (1995) · Science · doi:10.1126/science.270.5240.1326 · Cited by 5,273
Cellular survival: a play in three Akts
Datta, S. R., Brunet, A., & Greenberg, M. E. (1999) · Genes & Development · doi:10.1101/gad.13.22.2905 · Cited by 4,216
Nagase, H., & Woessner, J. F. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.31.21491 · Cited by 3,905
Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Dyk, D. E. V., Pitts, W. J., Earl, R. A., Hobbs, F. W., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.29.18623 · Cited by 3,016
Regulation of matrix metalloproteinase expression in tumor invasion
Westermarck, J. K., & Kähäri, V. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.8.781 · Cited by 1,494
Organization and regulation of mitogen-activated protein kinase signaling pathways
Garrington, T. P., & Johnson, G. L. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)80028-3 · Cited by 1,268
Activation of Mitogen-activated Protein Kinase by H2O2
Guyton, K. Z., Liu, Y., Gorospe, M., Xu, Q., & Holbrook, N. J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.8.4138 · Cited by 1,212
Metalloproteinases in biology and pathology of the nervous system
Yong, W. V., Power, C., Forsyth, P., & Edwards, D. (2001) · Nature Reviews Neuroscience · doi:10.1038/35081571 · Cited by 1,094
Asahi, M., Wang, X., Mori, T., Sumii, T., Jung, J.-C., Moskowitz, M. A., Fini, M. E., & Lo, E. H. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-19-07724.2001 · Cited by 1,004
Self-citationRosenberg, G. A., Estrada, E. Y., & Dencoff, J. E. (1998) · Stroke · doi:10.1161/01.str.29.10.2189 · Cited by 861
Research works printed but not linked: 1
- MUN-BRYCE S., 1998, Am. J. Physiol., 274, R1203
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Zhang, Y., Yang, X., Hou, X., Zhou, W., Bi, C., Yang, Z., Lu, S., Ding, Z., Ding, Z., Zou, Y. F., et al. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.828567 · Cited by 10
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Knoblach, S. M., & Faden, A. I. (2006) · Springer eBooks · doi:10.1007/0-387-23101-3_4 · Cited by 7
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Harris, L. K., Black, R. T., Reeves, T. M., & Phillips, L. L. (2012) · Springer protocols handbooks/Springer protocols · doi:10.1007/978-1-61779-576-3_12 · Cited by 4
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Ford, C. C., & Rosenberg, G. A. (2006) · Springer eBooks · doi:10.1007/0-387-23101-3_14 · Cited by 2
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Kang, W., & Hébert, J. M. (2011) · Cited by 1
Zhu, W., Hua, X., Liu, Z., Zhang, X., Li, S., & Jing, C. (2021) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2021.05.025 · Cited by 1
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Soliman, M. L., & Rosenberger, T. A. (2013) · Advances in Neuroimmune Biology · doi:10.3233/nib-130060 · Cited by 1
Augustine, C. (2013) · Scholarship@Western (Western University)
Vilalta, A. (2009) · TDX (Tesis Doctorals en Xarxa)
Matrix Metalloproteinases and Tissue Plasminogen Activator Reperfusion Therapy for Stroke
Ning, M., Montaner, J., Wang, X., Lee, S. ‐., Tsuji, K., Tejima, E., Buchan, A. M., & Lo, E. H. (2006) · Springer eBooks · doi:10.1007/978-0-387-30383-3_15
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Tubman, J. (2019) · Scholarship at UWindsor (University of Windsor)
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Wu, H., Zheng, J., Xu, W., Zhou, F., Lenahan, C., Giamas, G., Wang, C., Zhang, J., & Ji, J. (2026) · Cancer Gene Therapy · doi:10.1038/s41417-026-01027-6
Engin, A., & Engin, A. B. (2015) · Molecular and integrative toxicology · doi:10.1007/978-3-319-15630-9_2
Metadata
- Authors
- Mori, T., Wang, X., Aoki, T., & Lo, E. H.
- Affiliations
- Harvard University (US)
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2002-11
- Volume
- 19
- Issue
- 11
- Pages
- 1411-1419
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- OpenAlex
- W2078262785
- Cited by
- 129
- References
- 62
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 13 · 2012: 5
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01-NS38731, R01 NS-40529, R01 NS 37074, R01NS040529, R01NS037074, R01NS038731)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- MMP-9, MAPK/ERK pathway, traumatic brain injury, cerebral edema, blood-brain barrier disruption, MEK inhibition, U0126, controlled cortical impact
- MeSH terms
- Animals, Brain Injuries, Butadienes, Edema, Enzyme Inhibitors, Male, Mice, Inbred C57BL, Nitriles, Down-Regulation, Matrix Metalloproteinase 9, Mitogen-Activated Protein Kinases, Mice, Matrix Metalloproteinase Inhibitors
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