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The neuronal death induced by endotoxic shock but not that induced by excitatory amino acids requires TNF‐α
Author(s) -
De Bock Frédéric,
Derijard Benoît,
Dornand Jacques,
Bockaert Joël,
Rondouin Gérard
Publication year - 1998
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1998.00317.x
Subject(s) - excitotoxicity , glutamate receptor , neurotoxicity , tumor necrosis factor alpha , nitric oxide , nitric oxide synthase , pharmacology , nmda receptor , lipopolysaccharide , chemistry , receptor , biology , immunology , biochemistry , medicine , endocrinology , toxicity
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) γ, 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‐α). Indeed, TNF‐α antibodies and SB203580, an inhibitor of p38 stress kinase known to block TNF‐α 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‐γ, TNF‐α 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‐α synthesis and a modest activation of p38 stress kinase, neither TNF‐α 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.