Cited by 129Traumatic Brain Injury and Neurovascular DisturbancesProtease and Inhibitor MechanismsBarrier Structure and Function Studies

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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

Mori, Tatsuro, Wang, Xiaoying, Aoki, Toshiaki, Lo, Eng H.·2002·Journal of Neurotrauma

DOI 10.1089/089771502320914642

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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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Authors: Mori, T., Wang, X., Aoki, T., & Lo, E. H.
Affiliations: Harvard University (US)
ORCID: Wang, Xiaoying
Lo, Eng H.
Venue: Journal of Neurotrauma
Publisher: SAGE Publications
Published: 2002-11
Volume: 19
Issue: 11
Pages: 1411-1419
ISSN: 0897-7151 (ISSN-L)
1557-9042
DOI: 10.1089/089771502320914642
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
Licence: www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
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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Downregulation of Matrix Metalloproteinase-9 and Attenuation of Edema via Inhibition of ERK Mitogen Activated Protein Kinase in Traumatic Brain Injury

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