Increased oxidative stress brought on by pro-inflammatory cytokines in neurodegenerative processes and the protective role of nitrone-based free radical traps.
Nitrone-based free radical traps (NFTs) have been shown to be protective in several neurodegenerative models. Our research has strongly implicated that: A) several neurodegenerative conditions exhibit increased levels of pro-inflammatory cytokines which consequently result in increased levels of oxidative stress and B) that NFTs act in part by suppressing oxidative stress through suppression of the action of the cytokine cascade. Acquired Immune Deficiency Syndrome (AIDS) dementia complex (ADC) is one of several conditions where the data collected helped to develop these concepts. Novel observations include demonstration that IL-1beta acts on cultured brain glia cells to invoke protein nitration and oxidative stress and that low levels of PBN (alpha-phenyl tert-butyl nitrone) inhibit this effect. We interpret these data as indicating that PBN prevents IL-1beta mediated peroxynitrite formation. Additionally, we have found that the AIDS viral envelope protein gp120 upregulates mRNA for the cytokines TNF alpha and TNF beta in rat neonatal brain, and that PBN prevents this. Western blots of protein extracts showed upregulation of inducible nitric oxide synthase (iNOS) in gp120 treated neonatal rat brains, and that PBN prevented induction of this enzyme as well. These observations underscore the general concept that PBN inhibits the induction of genes which produce neurotoxic products, one of which is peroxynitrite formed by the reaction of nitric oxide with superoxide, and may act also by inhibiting the induction of cytokines which mediate pro-inflammatory conditions in the brain.
Floyd
R A
RA
Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Hensley
K
K
Jaffery
F
F
Maidt
L
L
Robinson
K
K
Pye
Q
Q
Stewart
C
C
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003497:Cyclic N-Oxides; D016207:Cytokines / Q000502:physiology*; D004594:Electrophysiology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012260:Ribonucleases / Q000378:metabolism; D013113:Spin Labels
D003497:Cyclic N-Oxides; D016207:Cytokines; D016166:Free Radical Scavengers; D015699:HIV Envelope Protein gp120; D009589:Nitrogen Oxides; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D012260:Ribonucleases