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.

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.

• Authors: 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
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 12 Pg. 64 (Apr 02 2015) ISSN: 1742-2094 [Electronic] England
• PMID: 25880399 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cholinesterase Inhibitors
• Cytokines
• Neuregulin-1
• Neuroprotective Agents
• RNA, Messenger
• Isoflurophate

Topics

• Animals
• Brain (pathology)
• Cholinesterase Inhibitors (therapeutic use, toxicity)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Encephalitis (chemically induced)
• Gene Expression Profiling
• Gene Expression Regulation (drug effects)
• Injections, Intra-Arterial
• Isoflurophate (toxicity)
• Male
• Microglia (drug effects, metabolism)
• Neuregulin-1 (therapeutic use)
• Neuroprotective Agents (therapeutic use)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger
• Rats
• Rats, Sprague-Dawley