Fleeting activation of ionotropic glutamate receptors sensitizes cortical neurons to complement attack.
Insidious attack of cortical neurons by complement has been implicated in Alzheimer's and other neurodegenerative diseases. Excitotoxicity, triggered by excessive activation of glutamate receptors, has been implicated in neuronal death following diverse insults, including ischemia and seizures. Clinical studies suggested that a minimal excitotoxic insult might sensitize neurons to complement attack. We found that fleeting activation of ionotropic glutamate receptors sensitizes neurons but not astrocytes to complement attack. The complement molecule effecting cytotoxicity was the membrane attack complex. The site within the complement cascade at which sensitization was effected was the membrane attack pathway. Sensitization mediated by glutamate receptor activation required Ca(2+)(o) and generation of reactive oxygen species. These in vitro findings predict that a fleeting excitotoxic insult could act synergistically with complement to destroy cortical neurons and accelerate neurological deterioration.
Xiong
Zhi Qi
ZQ
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
McNamara
James O
JO
D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000276:immunology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D018698:Glutamic Acid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D015938:Complement Membrane Attack Complex; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase