Cerebral vasculature is the major target of oxidative protein alterations in bacterial meningitis.
We have previously shown that antioxidants such as a-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or alpha-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations.
Institute for Infectious Diseases, University of Berne, Switzerland.
Manuela
M
Schaper
Suzanne
S
Gergely
Jens
J
Lykkesfeldt
Jakob
J
Zbären
Stephen L
SL
Leib
Martin G
MG
Täuber
Stephan
S
Christen
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003497:Cyclic N-Oxides; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D016920:Meningitis, Bacterial / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D013482:Superoxide Dismutase / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D003553:Cystine; D000429:Alcohol Oxidoreductases; D013482:Superoxide Dismutase; D005974:Glutamate-Ammonia Ligase; C027576:4-hydroxy-2-nonenal; C030905:N-monoacetylcystine