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

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