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

Journal of Neuroinflammation

Byron D Ford⁵  Monique C Surles-Zeigler⁵  Timothy J Distel⁵  Alicia S Gates⁵  Teclemichael Tewolde⁵  Donald A Bruun¹  Todd E White⁵  Kyndra C Stovall³  Cuimei Liu⁴  Gregory D Ford²  Pamela J Lein¹  Yonggang Li⁵ 

[1] Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis 95616, CA, USA;Department of Biology, Morehouse College, 830 Westview Drive SW, Atlanta 30310, GA, USA;Department of Physiology, Emory University, 201 Dowman Dr., Atlanta 30322, GA, USA;Institute of Infectious Disease, Xiangya Hospital, Central-South University, No.9 Chegongzhuang Avenue, Changsha 100044, China;Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta 30310, GA, USA

关键词: Rat model;    Nerve agent;    Neuroprotection;    Microarray;    Immunity;    Delayed neurotoxicity;    Cytokine;    Chemokine;    Apoptosis;   

Others  :  1227101
DOI  :  10.1186/s12974-015-0283-y

 received in 2014-12-19, accepted in 2015-03-17,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Li et al.; licensee BioMed Central.

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