Cited by 1,006Neuroinflammation and Neurodegeneration MechanismsNeurological Disorders and TreatmentsNeurological Disease Mechanisms and Treatments

Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia

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Yrjänheikki, Juha, Keinänen, Riitta, Pellikka, Milla, Hökfelt, Tomas, Koistinaho, Jari·1998·Proceedings of the National Academy of Sciences

Abstract

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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  1. [13]Amin, A. R., Attur, M. G., Thakker, G. D., Patel, P. D., Vyas, P. R., Patel, R. N., Patel. I. R. & Abramson, S. B. (1996) Proc. Natl. Acad. Sci. USA 93, 14014-14019.
  2. [39]Giulian, D. (1997) in Primer on Cerebrovascular Diseases , eds. Welch, K. M. A., Caplan, L. R., Reis, D. J., Siesjo ¨, B. K. & Weir, B. (Academic, New York) pp. 117-123.
  3. [47]Hara, H., Friedlander, R. M., Gagliardini, V., Auata, C., Fink, K., Huang, Z., Shimizu-Sasamata, M., Yuan, J. & Moskowitz, M. A. (1997) Proc. Natl. Acad. Sci. USA 94, 2007-2012.

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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
Venue
Proceedings of the National Academy of Sciences
Published
1998-12-22
Volume
95
Issue
26
Pages
15769-15774
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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