A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

Abstract

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2XLD50), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits.

Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups

“…An alternative explanation is that injury may be model-specific, perhaps related to the cholinergic nature of SE in the current model and it is uncertain whether it applies to other types of severe neonatal seizures (Holmes et al, 1998; Liu et al, 1999; Riviello et al, 2002). This would have implications for neonatal victims of SE induced by nerve agents or organophosphates, although the lack of lesions when neonatal SE is induced by nerve agents in experimental animals argues against that interpretation (Miller et al, 2015). At 6 h post-SE onset, we found mild but significant neuronal injury in neocortex, thalamus, CA3 and dentate gyrus of the dorsal hippocampal formation.…”

Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides

“…Particular emphasis must be placed on developing experimental paradigms to characterize the response of special populations to organophosphate exposure and potential treatments. Models that focus on the young and the elderly will help us to protect populations that are generally most vulnerable to toxic threats . We also need to begin utilizing the liberties that rodent models afford us, namely, the opportunity to directly manipulate neural circuits that may be involved in the generation and maintenance of SE .…”

“…Models that focus on the young and the elderly will help us to protect populations that are generally most vulnerable to toxic threats. 74 We also need to begin utilizing the liberties that rodent models afford us, namely, the opportunity to directly manipulate neural circuits that may be involved in the generation and maintenance of SE. 75,76 Techniques like neuroimaging, advanced EEG processing, and the use of genetically encoded markers of neuronal activity should help to guide us in the rational development of drugs that target specific cell populations and neural nuclei in the years to come.…”

Age-dependent behaviors, seizure severity and neuronal damage in response to nerve agents or the organophosphate DFP in immature and adult rats

“…These data suggest that there are age-specific effects of NAs and other OPs. However, while age-related responses to other chemoconvulsant agents have been investigated ( Cavalheiro et al, 1987 ; Haut et al, 2004 ; Scantlebury et al, 2007 ), and there are also electrographic and neuropathological characterizations of acute NA and OP poisoning in adult rats ( Crawford et al, 2004 ; Deshpande et al, 2010 ; McDonough et al, 1995 , 1998 ; Todorovic et al, 2012 ), characterizing the effects of these agents in immature animals has only just begun ( Fawcett et al, 2009 ; Miller et al, 2015 ; Shih et al, 1990 ; Wright et al, 2016 ). As there are evident differences in the seizures of patients based on their age, therapies administered to adults many not be optimal for children ( Baker, 2007 ; Rotenberg and Newmark, 2003 ).…”