Format

Send to

Choose Destination
J Neuroinflammation. 2015 Apr 2;12:64. doi: 10.1186/s12974-015-0283-y.

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

Author information

1
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. yli@msm.edu.
2
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. pjlein@ucdavis.edu.
3
Department of Biology, Morehouse College, 830 Westview Drive SW, Atlanta, GA, 30310, USA. gregory.ford@morehouse.edu.
4
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. Cuimeiliu@hotmail.com.
5
Institute of Infectious Disease, Xiangya Hospital, Central-South University, No.9 Chegongzhuang Avenue, Changsha, 100044, China. Cuimeiliu@hotmail.com.
6
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. kstovall@msm.edu.
7
Department of Biology, Morehouse College, 830 Westview Drive SW, Atlanta, GA, 30310, USA. kstovall@msm.edu.
8
Department of Physiology, Emory University, 201 Dowman Dr., Atlanta, GA, 30322, USA. kstovall@msm.edu.
9
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. twhite@msm.edu.
10
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. dabruun@ucdavis.edu.
11
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. ttwolde@msm.edu.
12
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. agates@msm.edu.
13
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. tdistel@msm.edu.
14
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. msurles@msm.edu.
15
Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA, 30310, USA. bford@msm.edu.

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.

PMID:
25880399
PMCID:
PMC4391606
DOI:
10.1186/s12974-015-0283-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center