Tumor necrosis factor-alpha 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 complement ary groups of experiments to evaluate the potential role s.of TNFa in a neo natal rodent model of excitotoxic injury, elicited by intracerebral injecti on of N-methyl-D-aspartate. We used immunohistochemistry and ELISA to evalu ate N-methyl-D-aspartate-induced changes in TNFa expression, and we co-inje cted TNFa with N-methyl-D-aspartate, to evaluate the effect of this cytokin e on the severity of tissue injury. Both intra-hippocampal and intra-striat al injection of N-methyl-D-aspartate 5 nmol.stimulated TNFa expression. Inc reased TNFa expression was detected 3-12 h after lesioning; TNFa was locali zed both in glial cells in the corpus callosum, and in cells with the morph ology 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-in jected with N-methyl-D-aspartate 5 or 10 nmol, TNFa 50 ng attenuated excito toxic 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-a spartate had no effect on the severity of the ensuing damage. The data indi cate that TNFa is rapidly produced in glial cells and neurons after an exci totoxic insult in the neonatal rat brain, and that administration of exogen ous TNFa results in region-specific attenuation of excitotoxic damage. We s peculate that endogenous TNFa may modulate the tissue response to excitotox ic injury in the developing brain. (C) 1999 Elsevier Science B.V. All right s reserved.