Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 261-269 |
| Number of pages | 9 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 253 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jun 15 2011 |
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Keywords
- Acute intoxication
- Delayed neurotoxicity
- DFP
- Neuronal injury
- Organophosphate
- Rat model
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Spatiotemporal pattern of neuronal injury induced by DFP in rats : A model for delayed neuronal cell death following acute OP intoxication. / Li, Yonggang; Lein, Pamela J; Liu, Cuimei; Bruun, Donald A.; Tewolde, Teclemichael; Ford, Gregory; Ford, Byron D.
In: Toxicology and Applied Pharmacology, Vol. 253, No. 3, 15.06.2011, p. 261-269.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Spatiotemporal pattern of neuronal injury induced by DFP in rats
T2 - A model for delayed neuronal cell death following acute OP intoxication
AU - Li, Yonggang
AU - Lein, Pamela J
AU - Liu, Cuimei
AU - Bruun, Donald A.
AU - Tewolde, Teclemichael
AU - Ford, Gregory
AU - Ford, Byron D.
PY - 2011/6/15
Y1 - 2011/6/15
N2 - 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.
AB - 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.
KW - Acute intoxication
KW - Delayed neurotoxicity
KW - DFP
KW - Neuronal injury
KW - Organophosphate
KW - Rat model
UR - http://www.scopus.com/inward/record.url?scp=79956327196&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79956327196&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2011.03.026
DO - 10.1016/j.taap.2011.03.026
M3 - Article
VL - 253
SP - 261
EP - 269
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -