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Nitric oxide-dependent damage to neuronal mitochondria involves the NMDA receptor
V C Stewart1, A J Heslegrave, G C Brown
1Division of Neurochemistry, Molecular Pathogenesis, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK. V.Stewart@ion.ucl.ac.uk
The European Journal of Neuroscience
|March 6, 2002
Summary
Astrocyte-derived nitric oxide (NO) triggers glutamate release, activating NMDA receptors and damaging neuronal mitochondria. This NO-induced excitotoxicity contributes to neurodegeneration.
Area of Science:
- Neuroscience
- Cellular Biology
- Biochemistry
Background:
- Cytokine-stimulated astrocytes produce nitric oxide (NO), which inhibits mitochondrial respiratory chain components.
- Previous studies showed prolonged exposure to astrocytic NO (48h) damages neuronal mitochondrial complexes II-IV, causing death.
Purpose of the Study:
- To investigate the role of glutamate and NMDA receptors in NO-induced neuronal mitochondrial damage.
- To elucidate the mechanism by which astrocyte-derived NO leads to neuronal death.
Main Methods:
- Co-culture of rat astrocytes and neurons.
- Exposure to nitric oxide donors (DETA-NONOate) and cytokine-stimulated astrocytes.
- Administration of NMDA receptor antagonist (MK-801).
- Measurement of glutamate release and mitochondrial respiratory chain complex activity.
Main Results:
- NMDA receptor antagonist MK-801 prevented NO-induced neuronal mitochondrial damage.
- Neurons incubated with NO-generating astrocytes showed enhanced glutamate release.
- Direct NO exposure damaged all neuronal mitochondrial complexes, an effect blocked by MK-801.
Conclusions:
- Astrocyte-derived NO activates neuronal NMDA receptors, leading to mitochondrial damage and neuronal death.
- This pathway involves glutamate release, NMDA receptor activation, and subsequent reactive nitrogen species formation.
- Glutamate, reactive nitrogen species, and mitochondrial dysfunction are implicated in neurodegenerative processes.