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Am J Physiol Cell Physiol 278: C144-C153, 2000;
0363-6143/00 $5.00
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Vol. 278, Issue 1, C144-C153, January 2000

Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide

Jie Liu, Irene Ginis, Maria Spatz, and John M. Hallenbeck

Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Brief "preconditioning" ischemia induces ischemic tolerance (IT) and protects the animal brain from subsequent otherwise lethal ischemia. Identification of the signaling steps most proximal to the development of the IT will allow induction of the resistance to ischemia shortly after the onset of stroke. Animal studies demonstrate a key role of tumor necrosis factor-alpha (TNF-alpha ) in induction of IT. The sphingolipid ceramide is known as a second messenger in many of the multiple effects of TNF-alpha . We hypothesized that ceramide could mediate IT. We demonstrate that preconditioning of rat cortical neurons with mild hypoxia protects them from hypoxia and O2-glucose deprivation injury 24 h later (50% protection). TNF-alpha pretreatment could be substituted for hypoxic preconditioning (HP). HP was attenuated by TNF-alpha -neutralizing antibody. HP and TNF-alpha pretreatment cause a two- to threefold increase of intracellular ceramide levels, which coincides with the state of tolerance. Fumonisin B1, an inhibitor of ceramide synthase, attenuated ceramide upregulation and HP. C-2 ceramide added to the cultures right before the hypoxic insult mimicked the effect of HP. Ceramide did not induce apoptosis. These results suggest that HP is mediated via ceramide synthesis triggered by TNF-alpha .

ischemia; hypoxia; tolerance; neurons; tumor necrosis factor-alpha


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