Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury

Background: neuregulin-1 (nrg-1) has been shown to act as a neuroprotectant in animal models of nerve agent intoxication and other acute brain injuries. we recently demonstrated that nrg-1 blocked delayed neuronal death in rats intoxicated with the organophosphate (op) neurotoxin diisopropylflurophosphate (dfp). it has been proposed that inflammatory mediators are involved in the pathogenesis of op neurotoxin-mediated brain damage. methods: we examined the influence of nrg-1 on inflammatory responses in the rat brain following dfp intoxication. microglial activation was determined by immunohistchemistry using anti-cd11b and anti-ed1 antibodies. gene expression profiling was performed with brain tissues using affymetrix gene arrays and analyzed using the ingenuity pathway analysis software. cytokine mrna levels following dfp and nrg-1 treatment was validated by real-time reverse transcription polymerase chain reaction (rt-pcr). results: dfp administration resulted in microglial activation in multiple brain regions,and this response was suppressed by treatment with nrg-1. using microarray gene expression profiling,we observed that dfp increased mrna levels of approximately 1,300 genes in the hippocampus 24 h after administration. nrg-1 treatment suppressed by 50% or more a small fraction of dfp-induced genes,which were primarily associated with inflammatory responses. real-time rt-pcr confirmed that the mrnas for pro-inflammatory cytokines interleukin-1β (il-1β) and interleukin-6 (il-6) were significantly increased following dfp exposure and that nrg-1 significantly attenuated this transcriptional response. in contrast,tumor necrosis factor α (tnfα) transcript levels were unchanged in both dfp and dfp + nrg-1 treated brains relative to controls. conclusion: neuroprotection by nrg-1 against op neurotoxicity is associated with the suppression of pro-inflammatory responses in brain microglia. these findings provide new insight regarding the molecular mechanisms involved in the neuroprotective role of nrg-1 in acute brain injuries. © li et al.; licensee biomed central.