Characterization of status epilepticus induced by two organophosphates in rats

Abstract

Organophosphates (OP) 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 200 nmol 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 4–18 hours after the end of paraoxon infusion. SE was also induced by peripheral subcutaneous injection of diisopropyl fluorophosphate (DFP, 1.25 mg/kg) or paraoxon (1.00 mg/kg) to rats pretreated with atropine (2 mg/kg) and 2-pralidoxime (2-PAM,50 mg/kg) 30 minutes prior to OP injection. SE occurred in 78% paraoxon–treated animals and in 79% of DFP-treated animals. Diazepam (10 mg/kg) was administered 10 min and 30 min 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 10 minutes after the onset of continuous EEG seizure activity but diazepam did not terminate SE in any animal when it was administered 30 minutes 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.

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

“…Indeed, the present study and previous studies (Shih and McDonough, 1999;de Araujo Furtado et al, 2010;McDonough et al, 2010;Langston et al, 2012;Todorovic et al, 2012;Apland et al, 2014) show that DZP can stop SE induced by nerve agents or other organophosphorus toxins, and results in a high survival rate. However, not only the antiseizure efficacy of DZP is reduced as the latency of administration from the onset of SE lengthens (Shih and McDonough, 1999;McDonough et al, 2010;Todorovic et al, 2012), but, importantly, this compound does not protect against brain damage. DZP has been used in adult rat models of nerve agent exposure as a means to stop ongoing nerve agent-induced SE and then study neuropathology (e.g.…”

“…Accordingly, benzodiazepines, which are positive allosteric modulators of GABAA receptors, are the first-line treatment of SE, regardless of its etiology (Cherian and Thomas, 2009;Trinka and Kälviäinen, 2017), and diazepam (DZP; a benzodiazepine) is the currently FDA-approved anticonvulsant for treating nerve agent-induced seizures. However, benzodiazepines are known to lose their efficacy as the latency of administration from the onset of SE increases (Walton and Treiman, 1991;Jones et al, 2002;Goodkin et al, 2003;Cherian and Thomas, 2009;McDonough et al, 2010;Todorovic et al, 2012;Niquet et al, 2016;Trinka and Kälviäinen, 2017); anticonvulsant efficacy at delayed post-SE-onset time points is necessary in a scenario of mass exposure to nerve agents, when medical assistance may not be available immediately. Furthermore, the neuroprotective efficacy of benzodiazepines is very limited (de Araujo Furtado et al, 2010;Langston, 2012;Apland et al, 2014).…”

The Limitations of Diazepam as a Treatment for Nerve Agent–Induced Seizures and Neuropathology in Rats: Comparison with UBP302

“…A number of concerns, however, are associated with the use of DZP for the cessation of nerve agent-induced SE. First, the efficacy of DZP decreases as the interval between the initiation of SE and the administration of DZP increases McDonough et al, 2010;Todorovic et al, 2012). This has also been documented in the lithiumpilocarpine model of SE (Walton and Treiman, 1988;Jones et al, 2002;Goodkin et al, 2003), which has many similarities to the nerve agent-induced SE, in both the mechanisms of seizure initiation and the effects it produces (Tetz et al, 2006).…”

Long-term Continuous EEG Monitoring in Small Rodent Models of Human Disease Using the Epoch Wireless Transmitter System

“…Status epilepticus can be induced in adult rats by injecting the animals with the organophosphate, DFP 22,23 . The data in Figure 5 show repetitive EEG discharges, which are indicative of status epilepticus (see temporal expansions Figure 5A, B).…”

“…Multiple channels of recording allow for the recording of multi-modal biopotentials, such as electrocardiogram and electroencephalogram. Animal models of co-morbidities will benefit by the ability to record biopotentials during behavior [21][22][23] . Combining behavior with EEG monitoring will provide researchers with a better tool for research and pre-clinical studies.…”