Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum

• Published in: Journal of neurochemistry 2003-12, Vol.87 (6), p.1518-1526
• Main Authors: Milatovic, Dejan, Zaja‐Milatovic, Snjeanna, Montine, Kathleen S., Horner, Philip J., Montine, Thomas J.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Biomarkers; Body Temperature - drug effects; Cell Count; Cyclic N-Oxides; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dendrites; Dendrites - drug effects; Dendrites - metabolism; Dinoprostone - metabolism; Docosahexaenoic Acids - pharmacokinetics; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; F4‐neuroprostanes; Female; Free Radical Scavengers - pharmacology; glia; Immunity, Innate; Immunohistochemistry - methods; Injections, Intraventricular; innate immunity; Lipopolysaccharides; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Neurological; Nerve Degeneration - chemically induced; Nerve Degeneration - prevention & control; neurodegeneration; Neuroglia - immunology; Neurology; Neurons - drug effects; Neurons - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitrogen Oxides - pharmacology; Oxidation-Reduction - drug effects; Peptides - genetics; Peptides - metabolism; Silver Staining - methods; spines; Telencephalon - cytology; Telencephalon - drug effects; Telencephalon - immunology; Time Factors; Tocopherols - pharmacology
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.02120.x

Activation of glial innate immunity is widely proposed to contribute to a number of degenerative and destructive diseases of brain. However, the precise role of activated innate immunity has been difficult to define in vivo because of multiple simultaneous pathogenic processes and responses to injury that confound interpretation of results from complex models of disease. Here, we used the model of intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) to test the hypothesis that directly activated glial innate immunity leads to neurodegeneration in cerebrum and to establish the molecular determinants of and neuroprotectants from such innate immunity‐mediated neuronal damage. Our results showed that ICV LPS induced delayed, reversible oxidative damage to cerebral neuronal membranes as measured by F4‐neuroprostanes that was coincident with degeneration of the hippocampal pyramidal neuron dendritic system, but not neuron death, in adult mice. Both neuronal oxidative damage and dendritic degeneration were NF‐κB and iNOS dependent and were completely suppressed by ibuprofen and α‐tocopherol, but not naproxen or γ‐tocopherol. These results prove that activation of glial innate immunity can lead to neurodegeneration independent of other pathologic processes, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and provide a possible explanation for the varying efficacy of neuroprotectants that have been suggested in observational studies of dementia.