Spatiotemporal pattern of neuronal injury induced by DFP in rats: A model for delayed neuronal cell death following acute OP intoxication

Yonggang Li, Pamela J Lein, Cuimei Liu, Donald A. Bruun, Teclemichael Tewolde, Gregory Ford, Byron D. Ford

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Organophosphate (OP) neurotoxins cause acute cholinergic toxicity and seizures resulting in delayed brain damage and persistent neurological symptoms. Testing novel strategies for protecting against delayed effects of acute OP intoxication has been hampered by the lack of appropriate animal models. In this study, we characterize the spatiotemporal pattern of cellular injury after acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats received pyridostigmine (0.1. mg/kg, im) and atropine methylnitrate (20. mg/kg, im) prior to DFP (9. mg/kg, ip) administration. All DFP-treated animals exhibited moderate to severe seizures within minutes after DFP injection but survived up to 72. h. AChE activity was significantly depressed in the cortex, hippocampus, subcortical brain tissue and cerebellum at 1. h post-DFP injection and this inhibition persisted for up to 72. h. Analysis of neuronal injury by Fluoro-Jade B (FJB) labeling revealed delayed neuronal cell death in the hippocampus, cortex, amygdala and thalamus, but not the cerebellum, starting at 4. h and persisting until 72. h after DFP treatment, although temporal profiles varied between brain regions. At 24. h post-DFP injection, the pattern of FJB labeling corresponded to TUNEL staining in most brain regions, and FJB-positive cells displayed reduced NeuN immunoreactivity but were not immunopositive for astrocytic (GFAP), oligodendroglial (O4) or macrophage/microglial (ED1) markers, demonstrating that DFP causes a region-specific delayed neuronal injury mediated in part by apoptosis. These findings indicate the feasibility of this model for testing neuroprotective strategies, and provide insight regarding therapeutic windows for effective pharmacological intervention following acute OP intoxication.

Original languageEnglish (US)
Pages (from-to)261-269
Number of pages9
JournalToxicology and Applied Pharmacology
Issue number3
StatePublished - Jun 15 2011


  • Acute intoxication
  • Delayed neurotoxicity
  • DFP
  • Neuronal injury
  • Organophosphate
  • Rat model

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology


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