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Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death
1Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Brain Research
|August 7, 1992
Summary
Inflammatory cytokines can harm brain cells through nitric oxide (NO) and reactive nitrogen oxides produced by microglia. This study reveals microglial NO and related substances as key neurotoxic agents in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- The precise role of inflammatory cytokines in neurological disease pathogenesis remains unclear.
- Cytokine-induced neurotoxicity may involve glial cell activation and the production of toxic nitric oxide (NO) and reactive nitrogen oxides.
Purpose of the Study:
- To investigate the mechanisms by which immunostimulated glial cells, particularly microglia, contribute to neurotoxicity.
- To identify the specific neurotoxic mediators involved in microglial-induced neuronal damage.
Main Methods:
- Utilized cultured microglia, meningeal fibroblasts, and Type 1 astrocytes stimulated with lipopolysaccharides and cytokines.
- Co-cultured immunostimulated microglia with cerebellar granule neurons to assess neurotoxicity.
- Employed NO synthase inhibitors (NG-nitroarginine), NO scavengers (oxyhemoglobin), NMDA receptor antagonists (MK-801, APV), and superoxide dismutase to elucidate mechanisms.
Main Results:
- Lipopolysaccharides and cytokines induced NO and reactive nitrogen oxide synthesis in microglia and meningeal fibroblasts, but not Type 1 astrocytes.
- Microglial-induced neurotoxicity in co-cultures was significantly reduced by NG-nitroarginine and oxyhemoglobin.
- Neurotoxicity was partially attenuated by NMDA receptor antagonists and augmented by superoxide dismutase, indicating a complex interplay of reactive species.
Conclusions:
- Immunostimulated microglia mediate neurotoxicity through the release of nitric oxide (NO), reactive nitrogen oxides, superoxide anion, and NMDA-like substances.
- Microglial-derived NO and reactive nitrogen oxides represent a significant neurotoxic pathway in neurodegenerative diseases.