Inflammation contributes to a wide variety of brain pathologies, apparently via glia killing neurons. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include iNOS (inducible nitric oxide synthase), which is expressed in glia only during inflammation, and PHOX (phagocytic NADPH oxidase) found in microglia and acutely activated by inflammation. High levels of iNOS expression in glia cause (i) NO (nitric oxide) inhibition of neuronal respiration, resulting in neuronal depolarization and glutamate release, followed by excitotoxicity, and (ii) glutamate release from astrocytes via calcium-dependent vesicular release. Hypoxia strongly synergizes with iNOS expression to induce neuronal death via mechanism (i), because NO inhibits cytochrome oxidase in competition with oxygen. Activation of PHOX (by cytokines, β-amyloid, prion protein, ATP or arachidonate) causes microglial proliferation and inflammatory activation; thus PHOX is a key regulator of inflammation. Activation of PHOX alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.
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November 2007
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Conference Article|
October 25 2007
Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase
G.C. Brown
G.C. Brown
1
1Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, U.K.
1email gcb@mole.bio.cam.ac.uk
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Publisher: Portland Press Ltd
Received:
June 08 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (5): 1119–1121.
Article history
Received:
June 08 2007
Citation
G.C. Brown; Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase. Biochem Soc Trans 1 November 2007; 35 (5): 1119–1121. doi: https://doi.org/10.1042/BST0351119
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