Dose–response effect of tetracyclines on cerebral matrix metalloproteinase-9 after vascular endothelial growth factor hyperstimulation.
Open accessAbstract
Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day ( P < 0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 ( P < 0.005) and further at more than 30 ( P < 0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day ( P < 0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day ( P < 0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.
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Minocycline can reduce plasma levels of MMP-9 and inhibit MMP-9 activity, suggesting a possible role of MMP-9 inhibition in the beneficial effects of minocycline in schizophrenia.
“Beside its antibiotic activity, minocycline can reduce plasma levels of MMP-9 (Dziembowska et al., 2013) and inhibit MMP-9 activity (Lee et al., 2006), suggesting a possible role of MMP-9 inhibition in the beneficial effects of minocycline in schizophrenia.”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Lee et al., 2006
Minocycline can reduce the levels and activity of MMP-9.
“Beside its antibiotic and anti-inflammatory activity, minocycline can reduce the levels and activity of matrix metalloproteinase-9 (MMP-9) (Lee et al., 2006; Bilousova et al., 2009; Dziembowska et al 2013).”
From Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome (2016) · cites this paper as Lee et al., 2006
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- Authors
- Lee, C. Z., Yao, J. S., Huang, Y., Zhai, W., Liu, W., Guglielmo, B. J., Lin, E., Yang, G.-Y., & Young, W. L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Young, William L
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2006-09
- Volume
- 26
- Issue
- 9
- Pages
- 1157-1164
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- OpenAlex
- W2073597522
- Cited by
- 78
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 1 · 2022: 7 · 2021: 4 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 5 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- University of California, San Francisco
- University Research Committee, Emory University
- National Institute of Neurological Disorders and Stroke (K24 NS 02091, R01NS027713, R01-NS 27713, K24NS002091)
- Topics
- Health Sciences › Medicine › Neurology › Vascular Malformations Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- tetracycline, doxycycline, minocycline, MMP-9, cerebral arteriovenous malformations, vascular endothelial growth factor, angiogenesis, dose-response relationship, ERK signaling, MMP-9 mRNA expression, brain drug levels
- MeSH terms
- Animals, Anti-Bacterial Agents, Brain, Brain Chemistry, Cell Movement, Cells, Cultured, Intracranial Arteriovenous Malformations, Dose-Response Relationship, Drug, Doxycycline, Gelatin, Male, Minocycline, Muscle, Smooth, Vascular, RNA, Messenger, Stimulation, Chemical, Tetracyclines, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Matrix Metalloproteinase 9, Vascular Endothelial Growth Factor A, Extracellular Signal-Regulated MAP Kinases, Mice
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