Neuroprotective mechanisms activated in non-seizing rats exposed to sarin

Brain Res. 2015 Aug 27;1618:136-48. doi: 10.1016/j.brainres.2015.05.034. Epub 2015 Jun 4.


Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures.

Keywords: Brain protection; MAPK signaling pathway; Microarray analysis; Sarin; Seizure; Whole-genome gene expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Cholinesterase Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Rats
  • Sarin / pharmacology*
  • Signal Transduction / drug effects
  • Time Factors
  • Transcription, Genetic / drug effects*


  • Cholinesterase Inhibitors
  • Sarin