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

Yonggang Li, Pamela J Lein, Gregory D. Ford, Cuimei Liu, Kyndra C. Stovall, Todd E. White, Donald A. Bruun, Teclemichael Tewolde, Alicia S. Gates, Timothy J. Distel, Monique C. Surles-Zeigler, Byron D. Ford

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number64
JournalJournal of Neuroinflammation
Volume12
Issue number1
DOIs
StatePublished - Apr 2 2015

Keywords

  • Apoptosis
  • Chemokine
  • Cytokine
  • Delayed neurotoxicity
  • Immunity
  • Microarray
  • Nerve agent
  • Neuroprotection
  • Rat model

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology

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    Li, Y., Lein, P. J., Ford, G. D., Liu, C., Stovall, K. C., White, T. E., Bruun, D. A., Tewolde, T., Gates, A. S., Distel, T. J., Surles-Zeigler, M. C., & Ford, B. D. (2015). Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury. Journal of Neuroinflammation, 12(1), [64]. https://doi.org/10.1186/s12974-015-0283-y