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The Journal of Neuroscience, September 1, 2001, 21(17):6480-6491
Inflammatory Neurodegeneration Mediated by Nitric Oxide from
Activated Glia-Inhibiting Neuronal Respiration, Causing Glutamate
Release and Excitotoxicity
Anna
Bal-Price and
Guy C.
Brown
Department of Biochemistry, University of Cambridge, Cambridge, CB2
1QW, United Kingdom
Glia undergo inflammatory activation in most CNS pathologies and
are capable of killing cocultured neurons. We investigated the
mechanisms of this inflammatory neurodegeneration using a mixed culture
of neurons, microglia, and astrocytes, either when the astrocytes were
activated directly with lipopolysaccharide (LPS) and interferon-
(IFN-) or LPS/IFN--activated microglia were added to mixed
neuronal cultures. In either case, activated glia caused 75-100%
necrotic cell death within 48 hr, which was completely prevented by
inhibitors of inducible nitric oxide synthase (iNOS) (aminoguanidine or
1400W). Activated astrocytes or microglia produced nitric oxide (NO)
(steady-state level ~0.5 µM), which immediately
inhibited the cellular respiration of cocultured neurons, as did
authentic NO. NO donors also decreased ATP levels and stimulated lactate production by neurons, consistent with NO-induced respiratory inhibition. NO donors or a specific respiratory inhibitor caused rapid
(<1 min) release of glutamate from neuronal and neuronal-astrocytic cultures and subsequent neuronal death that was blocked by an antagonist of NMDA receptor (MK-801). MK-801 also blocked neuronal death induced by activated glia. High oxygen also prevented NO-induced neuronal death, consistent with death being induced by NO inhibition of
cytochrome c oxidation in competition with oxygen. Thus
activated glia kill neurons via NO from iNOS, which inhibits neuronal
respiration resulting in glutamate release and subsequent
excitotoxicity. This may contribute to neuronal cell death in
inflammatory, infectious, ischemic, and neurodegenerative diseases.
Key words:
nitric oxide; mitochondria; astrocytes; microglia; neurons; inflammation
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176480-12$05.00/0
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