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Characterization of status epilepticus induced by two organophosphates in rats
Marko S Todorovic1, Morgan L Cowan, Corrinee A Balint
1Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
Abstract:
Organophosphates (OPs) inhibit the enzyme cholinesterase and cause accumulation of acetylcholine, and are known to cause seizures and status epilepticus (SE) in humans. The animal models of SE caused by organophosphate analogs of insecticides are not well characterized. SE caused by OPs paraoxon and diisopropyl fluorophosphate (DFP) in rats was characterized by electroencephalogram (EEG), behavioral observations and response to treatment with the benzodiazepine diazepam administered at various stages of SE. A method for SE induction using intrahippocampal infusion of paraoxon was also tested. Infusion of 200nmol paraoxon into the hippocampus caused electrographic seizures in 43/52 (82.7%) animals tested; and of these animals, 14/43 (30%) had self-sustaining seizures that lasted 4-18h after the end of paraoxon infusion. SE was also induced by peripheral subcutaneous injection of diisopropyl fluorophosphate (DFP, 1.25mg/kg) or paraoxon (1.00mg/kg) to rats pretreated with atropine (2mg/kg) and 2-pralidoxime (2-PAM, 50mg/kg) 30min prior to OP injection. SE occurred in 78% paraoxon-treated animals and in 79% of DFP-treated animals. Diazepam (10mg/kg) was administered 10min and 30min after the onset of continuous EEG seizures induced by paraoxon and it terminated SE in a majority of animals at both time points. DFP-induced SE was terminated in 60% animals when diazepam was administered 10min after the onset of continuous EEG seizure activity but diazepam did not terminate SE in any animal when it was administered 30min after the onset of continuous seizures. These studies demonstrate that both paraoxon and DFP can induce SE in rats but refractoriness to diazepam is a feature of DFP induced SE.
Insights
Organophosphates cause seizures and status epilepticus (SE). This study characterized SE models in rats using paraoxon and diisopropyl fluorophosphate (DFP), finding diazepam effective early but not for DFP-induced SE later.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Organophosphates (OPs) inhibit cholinesterase, leading to acetylcholine accumulation and seizures.
- Existing animal models for OP-induced status epilepticus (SE) require further characterization.
Purpose of the Study:
- To characterize SE induced by paraoxon and diisopropyl fluorophosphate (DFP) in rats.
- To evaluate the efficacy of diazepam in treating OP-induced SE at different time points.
Main Methods:
- SE was induced via intrahippocampal paraoxon infusion or subcutaneous injection of paraoxon/DFP in pretreated rats.
- Electroencephalogram (EEG) monitoring, behavioral observations, and diazepam treatment were employed.
- Treatment efficacy was assessed based on SE termination at 10 and 30 minutes post-seizure onset.
Main Results:
- Intrahippocampal paraoxon induced SE in 82.7% of rats, with 30% experiencing prolonged seizures.
- Subcutaneous paraoxon (78%) and DFP (79%) successfully induced SE in pretreated rats.
- Diazepam terminated SE in most cases when given 10 minutes after seizure onset for both OPs.
- Diazepam was ineffective for DFP-induced SE when administered 30 minutes after seizure onset.
Conclusions:
- Paraoxon and DFP are effective in inducing SE in rat models.
- DFP-induced SE exhibits refractoriness to diazepam when treatment is delayed.
- These findings highlight the importance of early intervention in OP-induced SE management.
