title: Neuregulin-1 inhibits neuroinflammatory responses in a rat model of organophosphate-nerve agent-induced delayed neuronal injury.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. yli@msm.edu.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. pjlein@ucdavis.edu.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
authors.affiliation: Department of Biology, Morehouse College, 830 Westview Drive SW, Atlanta, GA, 30310, USA. gregory.ford@morehouse.edu.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ford
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. Cuimeiliu@hotmail.com.|Institute of Infectious Disease, Xiangya Hospital, Central-South University, No.9 Chegongzhuang Avenue, Changsha, 100044, China. Cuimeiliu@hotmail.com.
authors.forename: Cuimei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. kstovall@msm.edu.|Department of Biology, Morehouse College, 830 Westview Drive SW, Atlanta, GA, 30310, USA. kstovall@msm.edu.|Department of Physiology, Emory University, 201 Dowman Dr., Atlanta, GA, 30322, USA. kstovall@msm.edu.
authors.forename: Kyndra C
authors.initials: KC
authors.lastname: Stovall
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. twhite@msm.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: White
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. dabruun@ucdavis.edu.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Bruun
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. ttwolde@msm.edu.
authors.forename: Teclemichael
authors.initials: T
authors.lastname: Tewolde
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. agates@msm.edu.
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Gates
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. tdistel@msm.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Distel
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. msurles@msm.edu.
authors.forename: Monique C
authors.initials: MC
authors.lastname: Surles-Zeigler
authors.affiliation: Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. bford@msm.edu.
authors.forename: Byron D
authors.initials: BD
authors.lastname: Ford
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007269:Injections, Intra-Arterial; D007531:Isoflurophate / Q000633:toxicity*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D020890:Neuregulin-1 / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D016207:Cytokines; D020890:Neuregulin-1; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D007531:Isoflurophate