Spatiotemporal pattern of neuronal injury induced by DFP in rats: A model for delayed neuronal cell death following acute OP intoxication
- Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310 (United States)
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616 (United States)
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. - Research Highlights: > DFP induced neuronal FJB labeling starting at 4-8 h after treatment > The pattern of DFP-induced FJB labeling closely corresponded to TUNEL staining > FJB-positive cells displayed reduced NeuN immunoreactivity > FJB-positive cells were not immunopositive for GFAP, O4 or ED1 cell markers
- OSTI ID:
- 21587770
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 253; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ANIMAL CELLS
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AUTONOMIC NERVOUS SYSTEM AGENTS
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CENTRAL NERVOUS SYSTEM
CEREBELLUM
CONNECTIVE TISSUE CELLS
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DISEASES
DRUGS
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HALOGEN COMPOUNDS
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PHOSPHORUS COMPOUNDS
RATS
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THALAMUS
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