Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia
Open accessAbstract
Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inflammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils. Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia. The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively. Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis. Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1beta-converting enzyme, a caspase that is induced in microglia after ischemia. Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals. Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult. Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.
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- Authors
- Yrjänheikki, J., Keinänen, R., Pellikka, M., Hökfelt, T., & Koistinaho, J.
- Affiliations
- University of Eastern Finland (FI)
- A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland; and Department of Neuroscience, Karolinska Institute, S-171-77, Stockholm, Sweden
- ORCID
- Hökfelt, Tomas
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-12-22
- Volume
- 95
- Issue
- 26
- Pages
- 15769-15774
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC28119
- OpenAlex
- W2036717742
- Cited by
- 1,006
- References
- 49
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 26 · 2023: 17 · 2022: 21 · 2021: 30 · 2020: 31 · 2019: 28 · 2018: 28 · 2017: 31 · 2016: 33 · 2015: 43 · 2014: 39 · 2013: 67 · 2012: 49
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- tetracycline, minocycline, doxycycline, global cerebral ischemia, ischemic stroke, neuroprotection, microglial activation, neuroinflammation, hippocampal neurons, CA1 pyramidal neurons, interleukin-1 beta converting enzyme, inducible nitric oxide synthase
- MeSH terms
- Animals, Ischemic Attack, Transient, Doxycycline, Gerbillinae, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Male, Minocycline, RNA, Messenger, Tetracyclines, Transcription, Genetic, Microglia, Pyramidal Cells, Neuroprotective Agents, Reverse Transcriptase Polymerase Chain Reaction
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