Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia
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Minocycline, a semisynthetic tetracycline derivative, protects brain against global and focal ischemia in rodents. We examined whether minocycline reduces excitotoxicity in primary neuronal cultures. Minocycline (0.02 microm) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 microm glutamate or 100 microm kainate for 24 hr. Treatment with these excitotoxins induced a dose-dependent proliferation of microglia that was associated with increased release of interleukin-1beta (IL-1beta) and was followed by increased lactate dehydrogenase (LDH) release. The excitotoxicity was enhanced when microglial cells were cultured on top of SC cultures. Minocycline prevented excitotoxin-induced microglial proliferation and the increased release of nitric oxide (NO) metabolites and IL-1beta. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1beta also in pure microglia cultures, and these responses were inhibited by minocycline. In both SC and pure microglia cultures, excitotoxins activated p38 mitogen-activated protein kinase (p38 MAPK) exclusively in microglia. Minocycline inhibited p38 MAPK activation in SC cultures, and treatment with SB203580, a p38 MAPK inhibitor, but not with PD98059, a p44/42 MAPK inhibitor, increased neuronal survival. In pure microglia cultures, glutamate induced transient activation of p38 MAPK, and this was inhibited by minocycline. These findings indicate that the proliferation and activation of microglia contributes to excitotoxicity, which is inhibited by minocycline, an antibiotic used in severe human infections.
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Inhibiting microglial activation may limit BBB disruption and reduce vasogenic edema in ischemic stroke, reducing ischemic tissue volume and neuronal deficits, and preventing hemorrhagic transformation.
“Inhibiting microglial activation may limit BBB disruption and reduce vasogenic edema in the context of ischemic stroke, reducing the volume of ischemic tissue and neuronal deficits, as well as preventing hemorrhagic transformation (Tikka et al., 2001; Yenari et al., 2006).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Tikka et al., 2001
Minocycline inhibits activation of microglia and brain infiltrating blood-derived macrophages and protects cultured neurons from excitotoxic insults by preventing microglial generation of glutamate, IL-1β and NO.
“minocycline, a member of the tetracycline antibiotic family, inhibits activation of microglia and brain infiltrating blood-derived macrophages and protects cultured neurons from excitotoxic insults by preventing microglial generation of glutamate, IL-1β and NO (Yrjänheikki et al., 1998, 1999; Tikka et al., 2001).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Tikka et al., 2001
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 Tikka et al., 2001
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- Authors
- Tikka, T., Fiebich, B. L., Goldsteins, G., Keinänen, R., & Koistinaho, J.
- Affiliations
- University of Eastern Finland (FI)
- University of Freiburg (DE)
- ORCID
- Fiebich, Bernd L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-04-15
- Volume
- 21
- Issue
- 8
- Pages
- 2580-2588
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762519
- OpenAlex
- W2113617025
- Cited by
- 958
- References
- 54
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 21 · 2023: 17 · 2022: 29 · 2021: 34 · 2020: 32 · 2019: 30 · 2018: 40 · 2017: 32 · 2016: 38 · 2015: 42 · 2014: 50 · 2013: 40 · 2012: 49
- FWCI
- 23.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Suomen Kulttuurirahasto
- Saastamoisen säätiö
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- minocycline, tetracycline derivatives, neuroprotection, excitotoxicity, microglial activation, microglial proliferation, glutamate, kainic acid, IL-1β, nitric oxide, p38 MAPK, spinal cord neurons, neuronal survival, neuroinflammation
- MeSH terms
- Animals, Anti-Bacterial Agents, Cell Division, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Inhibitors, Hydro-Lyases, Imidazoles, Kainic Acid, Minocycline, Pyridines, Spinal Cord, Cell Death, Rats, Wistar, Microglia, Neuroprotective Agents, Glutamic Acid, Excitatory Amino Acids, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Rats
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