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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González-Mariscal, L., Tapia, R., & Chamorro, D. (2008) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.08.018 · Cited by 759
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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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