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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia
1A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Abstract:
Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-D-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke. Minocycline, a tetracycline derivative with antiinflammatory effects, inhibits IL-1beta-converting enzyme and inducible nitric oxide synthase up-regulation in animal models of ischemic stroke and Huntington's disease and is therapeutic in these disease animal models. Here we report that nanomolar concentrations of minocycline protect neurons in mixed spinal cord cultures against NMDA excitotoxicity. NMDA treatment alone induced microglial proliferation, which preceded neuronal death, and administration of extra microglial cells on top of these cultures enhanced the NMDA neurotoxicity. Minocycline inhibited all these responses to NMDA. Minocycline also prevented the NMDA-induced proliferation of microglial cells and the increased release of IL-1beta and nitric oxide in pure microglia cultures. Finally, minocycline inhibited the NMDA-induced activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells, and a specific p38 MAPK inhibitor, but not a p44/42 MAPK inhibitor, reduced the NMDA toxicity. Together, these results suggest that microglial activation contributes to NMDA excitotoxicity and that minocycline, a tetracycline derivative, represents a potential therapeutic agent for brain diseases.
Insights
Minocycline protects neurons from glutamate excitotoxicity by inhibiting microglial activation. This tetracycline derivative offers a potential therapeutic strategy for neurodegenerative diseases and stroke.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Glutamate excitotoxicity via N-methyl-D-aspartate (NMDA) receptors contributes to neurodegeneration and stroke.
- Minocycline, an anti-inflammatory tetracycline derivative, shows therapeutic potential in animal models.
Purpose of the Study:
- To investigate the neuroprotective effects of minocycline against NMDA-induced excitotoxicity.
- To elucidate the role of microglial activation in NMDA excitotoxicity and minocycline's mechanism of action.
Main Methods:
- Primary neuronal and microglial cultures were used to assess NMDA excitotoxicity.
- Minocycline's effects on microglial proliferation, cytokine release (IL-1beta), nitric oxide production, and p38 MAPK activation were evaluated.
- Specific p38 MAPK inhibitors were employed to confirm its role.
Main Results:
- Minocycline protected neurons from NMDA excitotoxicity at nanomolar concentrations.
- NMDA treatment induced microglial proliferation and enhanced neurotoxicity, effects inhibited by minocycline.
- Minocycline suppressed NMDA-induced microglial activation, IL-1beta release, nitric oxide production, and p38 MAPK phosphorylation.
Conclusions:
- Microglial activation is a key contributor to NMDA excitotoxicity.
- Minocycline mitigates NMDA excitotoxicity by inhibiting microglial activation and downstream signaling pathways.
- Minocycline represents a promising therapeutic candidate for conditions involving NMDA excitotoxicity.
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