4-hydroxy-2-nonenal and Meningitis--Bacterial

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.

Topics: Alcohol Oxidoreductases; Aldehydes; Animals; Antioxidants; Cerebral Arteries; Cyclic N-Oxides; Cystine; Encephalitis; Female; Free Radical Scavengers; Glutamate-Ammonia Ligase; Lipid Peroxidation; Meningitis, Bacterial; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Nitrogen Oxides; Oxidative Stress; Rats; Reactive Oxygen Species; Streptococcus pneumoniae; Superoxide Dismutase

To study reactive nitrogen species-mediated oxidative brain damage and antioxidant defenses in patients with acute bacterial meningitis.. Nitrotyrosine (a widely used marker for the formation of reactive nitrogen species, such as peroxynitrite) and the lipid peroxidation product 4-hydroxynonenal were detected by immunohistochemistry in brain specimens obtained at autopsy. CSF concentrations of nitrotyrosine were quantified by ELISA. CSF and serum concentrations of ascorbic acid, uric acid, and its oxidation product allantoin were determined by high-pressure liquid chromatography.. Tyrosine nitration was strongly increased during meningitis. It was most evident in inflammatory cells and blood vessels in the subarachnoid space. The same cell types stained positive for the lipid peroxidation marker 4-hydroxynonenal, suggesting that reactive nitrogen species contribute to oxidative brain damage during meningitis. High CSF nitrotyrosine concentrations were associated with an unfavorable outcome according to the Glasgow Outcome Score. In the CSF, the increase of nitrotyrosine was accompanied by a depletion of the antioxidant ascorbic acid and an increased oxidation of the natural peroxynitrite scavenger uric acid to allantoin.. These findings indicate that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are involved in the pathophysiology of bacterial meningitis in humans.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldehydes; Allantoin; Ascorbic Acid; Brain; Cysteine Proteinase Inhibitors; Female; Free Radical Scavengers; Glasgow Outcome Scale; Humans; Immunohistochemistry; Male; Meningitis, Bacterial; Middle Aged; Neurons; Oxidative Stress; Reactive Nitrogen Species; Statistics as Topic; Treatment Outcome; Tyrosine; Uric Acid

Animal studies of experimental bacterial meningitis have provided evidence for an involvement of reactive oxygen species (ROS) in the pathophysiology of this disease. Using a lucigenin-enhanced chemiluminescence (CL) method, we tested whether primary rat cerebral endothelial cells can be induced to release ROS upon stimulation with pneumococci. In addition, we determined CSF levels of two markers of lipid peroxidation in patients with bacterial meningitis, compared to patients with viral meningitis and noninflammatory neurological disorders. Malondialdehyde/4-hydroxynonenal concentrations were significantly elevated in CSF samples obtained from patients with bacterial meningitis (23.12+/-5.47 microM), as compared to both control groups (5.43+/-0.18 microM and 7.80+/-0.33 microM, respectively). Cerebromicrovascular endothelial cells, granulocytes, and the macrophage cell line RAW 264.7 (but not astrocytes and neuron-like cells) produced an increase in CL intensity after stimulation with pneumococci. The peak value produced by endothelial cells (500+/-83 cpm) was significantly lower than the maximum CL response in macrophages (1386+/-142 cpm; p<0.05). After addition of superoxide dismutase (SOD), the CL signal returned to baseline values. Equal to the CL technique, nitroblue tetrazolium (NBT) staining of RAW 264.7 showed SOD-inhibitable formazan precipitation when stimulated with pneumococci. In conclusion, this study suggests an important role of endothelial cells in the pathophysiology of bacterial meningitis-namely as a source for ROS production.

Topics: Acridines; Adult; Aged; Aged, 80 and over; Aldehydes; Animals; Cerebrovascular Circulation; Endothelium, Vascular; Female; Humans; Luminescent Measurements; Male; Malondialdehyde; Meningitis, Bacterial; Mice; Middle Aged; Pneumococcal Infections; Rats; Rats, Wistar; Superoxides