The chemical convulsant diisopropylfluorophosphate (DFP) causes persistent neuropathology in adult male rats independent of seizure activity

Eduardo A. González, Alexa C. Rindy, Michelle A. Guignet, Jonas J. Calsbeek, Donald A. Bruun, Ashish Dhir, Peter Andrew, Naomi Saito, Douglas J. Rowland, Danielle J. Harvey, Michael A. Rogawski, Pamela J. Lein

Research output: Contribution to journalArticle

Abstract

Organophosphate (OP) threat agents can trigger seizures that progress to status epilepticus, resulting in persistent neuropathology and cognitive deficits in humans and preclinical models. However, it remains unclear whether patients who do not show overt seizure behavior develop neurological consequences. Therefore, this study compared two subpopulations of rats with a low versus high seizure response to diisopropylfluorophosphate (DFP) to evaluate whether acute OP intoxication causes persistent neuropathology in non-seizing individuals. Adult male Sprague Dawley rats administered DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im), and pralidoxime (25 mg/kg, im) were monitored for seizure activity for 4 h post-exposure. Animals were separated into groups with low versus high seizure response based on behavioral criteria and electroencephalogram (EEG) recordings. Cholinesterase activity was evaluated by Ellman assay, and neuropathology was evaluated at 1, 2, 4, and 60 days post-exposure by Fluoro-Jade C (FJC) staining and micro-CT imaging. DFP significantly inhibited cholinesterase activity in the cortex, hippocampus, and amygdala to the same extent in low and high responders. FJC staining revealed significant neurodegeneration in DFP low responders albeit this response was delayed, less persistent, and decreased in magnitude compared to DFP high responders. Micro-CT scans at 60 days revealed extensive mineralization that was not significantly different between low versus high DFP responders. These findings highlight the importance of considering non-seizing patients for medical care in the event of acute OP intoxication. They also suggest that OP intoxication may induce neurological damage via seizure-independent mechanisms, which if identified, might provide insight into novel therapeutic targets.

Original languageEnglish (US)
JournalArchives of Toxicology
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • Diisopropylfluorophosphate
  • Micro-CT
  • Neurodegeneration
  • Organophosphate neurotoxicity
  • Status epilepticus

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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