Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum.
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-kappaB and iNOS dependent and were completely suppressed by ibuprofen and alpha-tocopherol, but not naproxen or gamma-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.
Milatovic
Dejan
D
Department of Pathology, University of Washington, Harborview Medical Center, Seattle, Washington 98104, USA.
Zaja-Milatovic
Snjeanna
S
Montine
Kathleen S
KS
Horner
Philip J
PJ
Montine
Thomas J
TJ
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers; D001831:Body Temperature / Q000187:drug effects; D002452:Cell Count; D003497:Cyclic N-Oxides; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007113:Immunity, Innate; D007150:Immunohistochemistry / Q000379:methods; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009457:Neuroglia / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D024505:Tocopherols / Q000494:pharmacology
D015415:Biomarkers; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D009589:Nitrogen Oxides; D010455:Peptides; C118258:SN50 peptide; D004281:Docosahexaenoic Acids; C029217:phenyl-N-tert-butylnitrone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015232:Dinoprostone; D024505:Tocopherols