Tumor necrosis factor-α attenuates N-methyl-D-aspartate-mediated neurotoxicity in neonatal rat hippocampus

Tumor necrosis factor-a TNFa.has been implicated in the pathophysiology of acute neonatal brain injury. We hypothesized that acute brain injury would induce TNFa expression and that exogenous TNFa would influence the severity of N-methyl-D-asparlate-induced tissue damage. We performed two complementary groups of experiments to evaluate the potential role s.of TNFa in a neonatal rodent model of excitotoxic injury, elicited by intracerebral injection of N-methyl-D-aspartate. We used immunohistochemistry and ELISA to evaluate N-methyl-D-aspartate-induced changes in TNFa expression, and we co-injected TNFa with N-methyl-D-aspartate, to evaluate the effect of this cytokine on the severity of tissue injury. Both intra-hippocampal and intra-striatal injection of N-methyl-D-aspartate 5 nmol.stimulated TNFa expression. Increased TNFa expression was detected 3-12 h after lesioning; TNFa was localized both in glial cells in the corpus callosum, and in cells with the morphology of interneurons in the ipsilateral hippocampus, striatum, cortex ana thalamus. Intra-hippocampal or Intra-striatal administration or TNFa 50 ng.alone did not elicit neuropathologic damage. In the hippocampus, when co-injected with N-methyl-D-aspartate 5 or 10 nmol, TNFa 50 ng attenuated excitotoxic injury by 35%-57%, compared to controls co-injected with heat-treated TNFa. in contrast; in the striatum, co-injection of TNFa with N-methyl-D-aspartate had no effect on the severity of the ensuing damage. The data indicate that TNFa is rapidly produced in glial cells and neurons after an excitotoxic insult in the neonatal rat brain, and that administration of exogenous TNFa results in region-specific attenuation of excitotoxic damage. We speculate that endogenous TNFa may modulate the tissue response to excitotoxic injury in the developing brain. (C) 1999 Elsevier Science B.V. All rights reserved.