Region‐selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

• Published in: Journal of neurochemistry 2002-08, Vol.82 (4), p.924-934
• Main Authors: Biegon, A., Alvarado, M., Budinger, T. F., Grossman, R., Hensley, K., West, M. S., Kotake, Y., Ono, M., Floyd, R. A.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Antioxidants - administration & dosage; Antioxidants - therapeutic use; Autoradiography; Binding, Competitive - drug effects; Brain - drug effects; Brain - metabolism; Brain - pathology; Cyclic N-Oxides; Disease Models, Animal; Dizocilpine Maleate - analogs & derivatives; Dizocilpine Maleate - pharmacokinetics; Drug Administration Routes; Encephalitis - chemically induced; Encephalitis - drug therapy; Encephalitis - metabolism; Encephalitis - pathology; endotoxin; Excitatory Amino Acid Antagonists - pharmacokinetics; glutamate; Isoquinolines - pharmacokinetics; Lipopolysaccharides; Male; meningitis; Microglia - pathology; Nitrogen Oxides - administration & dosage; Nitrogen Oxides - therapeutic use; NMDA receptors; peripheral benzodiazepine receptors; Rats; Rats, Wistar; Receptors, GABA-A - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Tissue Distribution - drug effects
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.01050.x

Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl‐tert‐butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hafter endotoxin injection. Animals were killed 7 days post‐injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open‐channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (two‐ to threefold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (> 50%) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl‐tert‐butyl nitrone treatment resulted in a partial inhibition (approx. 25% decrease) of the lipopolysaccharide‐induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide‐induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.