Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice
Open accessAbstract
Minocycline is protective in models of transient middle cerebral artery occlusion (MCAO). We studied whether minocycline and doxycycline, another tetracycline derivative, provide protection in permanent MCAO. Because minocycline inhibits matrix metalloprotease-9 (MMP-9), we also compared minocycline's protective effect in wild type (wt) and MMP-9 knock-out (ko) mice. Wt FVB/N, Balb/C, and two lines of MMP-9 ko and their wt C57Bl/6 control mice were subjected to 24- or 72-hour permanent MCAO. Drug administration was started either 12 hours before or 2 hours after the onset of MCAO. Infarct size was determined by triphenyltetrazolium staining or T2-weighted MRI. Zymography was used to study the expression of MMPs. In wt strains, tetracycline treatments started before MCAO reduced the infarct size by 25% to 50%, whereas the treatment started after MCAO was not protective. Minocycline inhibited ischemia-provoked pro-MMP-9 induction in wt mice, but was not protective in MMP-9 ko mice. Pro-MMP-2 was induced by MCAO in wt and MMP-9 ko mice. MCAO-induced pro-MMP-2 was downregulated by minocycline treatment in wt mice but remained in MMP-9 ko mice at the same level as in saline-treated wt mice. Tetracyclines are protective in permanent MCAO when the treatment is started before the insult. Minocycline may provide protection by interfering with MMPs.
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Anti-inflammatory properties of minocycline are thought to act through inhibition of p38MAPK and MMP-9.
“These anti-inflammatory properties of minocycline are thought to act through inhibition of p38MAPK and MMP-9 (Tikka et al., 2001; Koistinaho et al., 2005).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Koistinaho et al., 2005
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- Authors
- Koistinaho, M., Malm, T. M., Kettunen, M. I., Goldsteins, G., Starckx, S., Kauppinen, R. A., Opdenakker, G., & Koistinaho, J.
- Affiliations
- University of Eastern Finland (FI)
- Rega Institute for Medical Research (BE)
- Department of Neurobiology, AI Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland
- Corresponding author
- Koistinaho, Milla
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2005-04
- Volume
- 25
- Issue
- 4
- Pages
- 460-467
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- OpenAlex
- W2004309874
- Cited by
- 120
- References
- 38
- Citations by year
- 2026: 2 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 8 · 2016: 2 · 2015: 10 · 2014: 12 · 2013: 11 · 2012: 7
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- minocycline, doxycycline, tetracycline, MMP-9, MMP-9 knockout mice, permanent cerebral ischemia, middle cerebral artery occlusion, neuroprotection, infarct size, MMP-2, timing of drug administration
- MeSH terms
- Animals, Anti-Bacterial Agents, Cerebral Cortex, Brain Ischemia, Doxycycline, Male, Mice, Inbred BALB C, Minocycline, Down-Regulation, Mice, Knockout, Infarction, Middle Cerebral Artery, Matrix Metalloproteinase 9, Mice, Matrix Metalloproteinase Inhibitors
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