Neuroprotective mechanisms activated in non-seizing rats exposed to sarin.

Abstract

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.

• Authors: Jerez A Te, Kimberly D Spradling-Reeves, James F Dillman 3rd, Anders Wallqvist
• Journal: Brain research (Brain Res) Vol. 1618 Pg. 136-48 (Aug 27 2015) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 26049129 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier B.V.

Chemical References

• Cholinesterase Inhibitors
• Sarin

Topics

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