The neuronal death induced by endotoxic shock but not that induced by excitatory amino acids requires TNF-alpha.
We studied, using organotypic hippocampal slices in culture, the role of pro-inflammatory cytokines, oxygen radicals and nitric oxide in neuronal death induced either by endotoxic insult [interferon (IFN) gamma, 24 h followed by lipopolysaccharide, 24 h] or by glutamate receptor-mediated excitotoxic insult. We demonstrated that neuronal death induced by endotoxic insult was absolutely dependent on the synthesis of tumour necrosis factor alpha (TNF-alpha). Indeed, TNF-alpha antibodies and SB203580, an inhibitor of p38 stress kinase known to block TNF-alpha and other cytokine synthesis, completely protected neurons from the endotoxic insult. Inhibiting oxygen radical and nitric oxide productions also reduced the endotoxic shock. We also showed that after priming the cultures with IFN-gamma, TNF-alpha was unable to induce neuronal death unless oxygen-free radicals were exogenously provided. In contrast, although glutamate receptor-induced excitotoxicity was associated with a low TNF-alpha synthesis and a modest activation of p38 stress kinase, neither TNF-alpha antibodies nor SB203580 were able to decrease excitotoxic neuronal insult. We did not reduce glutamate receptor-induced neuronal death with superoxide dismutase plus catalase. In conclusion, although inflammation follows glutamate receptor-mediated neurotoxicity, the mechanisms by which an endotoxic insult triggers neuronal death are different from those involved in excitotoxicity.
de Bock
F
F
CNRS, UPR 9023, Laboratoire de Médecine Expérimentale, Institut de Biologie, Montpellier, France. debock@ccipe.montp.inserm.fr
Derijard
B
B
Dornand
J
J
Bockaert
J
J
Rondouin
G
G
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018846:Excitatory Amino Acids / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D007371:Interferon-gamma / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017382:Reactive Oxygen Species / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D018846:Excitatory Amino Acids; D005609:Free Radicals; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D017470:Receptors, Glutamate; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D016202:N-Methylaspartate; D007371:Interferon-gamma; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007608:Kainic Acid