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

Scholl, Erika A.; Miller-Smith, Stephanie M.; Bealer, Steven L.; Lehmkuhle, Mark J.; Ekstrand, Jeffrey J.; Dudek, F. Edward; McDonough, John H.

doi:10.1016/j.neuro.2018.02.018

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

Journal Article · Tue May 01 00:00:00 EDT 2018 · Neurotoxicology

DOI:https://doi.org/10.1016/j.neuro.2018.02.018· OSTI ID:1623702

Scholl, Erika A. ^[1]; Miller-Smith, Stephanie M. ^[2]; Bealer, Steven L. ^[3]; Lehmkuhle, Mark J. ^[4]; Ekstrand, Jeffrey J. ^[5]; Dudek, F. Edward ^[6]; McDonough, John H. ^[2]

Univ. of Utah, Salt Lake City, UT (United States). Department of Neurosurgery; DOE/OSTI
Aberdeen Proving Ground, MD (United States). Neuroscience Branch, U.S. Army Medical Research Institute of Chemical Defense
Univ. of Utah, Salt Lake City, UT (United States). Department of Neurosurgery; Univ. of Utah, Salt Lake City, UT (United States). Department of Pharmacology and Toxicology
Univ. of Utah, Salt Lake City, UT (United States). Department of Neurosurgery; Epitel, Inc., Salt Lake City, UT (United States)
Univ. of Utah, Salt Lake City, UT (United States). Department of Pediatrics
Univ. of Utah, Salt Lake City, UT (United States). Department of Neurosurgery

Exposure to nerve agents (NAs) and other organophosphates (OPs) can initiate seizures that rapidly progress to status epilepticus (SE). While the electrographic and neuropathological sequelae of SE evoked by NAs and OPs have been characterized in adult rodents, they have not been adequately investigated in immature animals. In this study postnatal day (PND) 14, 21 and 28 rat pups, along with PND70 animals as adult controls, were exposed to NAs (sarin, VX) or another OP (diisopropylfluorophosphate, DFP). We then evaluated behavioral and electrographic (EEG) correlates of seizure activity, and performed neuropathology using Fluoro-Jade B. Although all immature rats exhibited behaviors that are often characterized as seizures, the incidence, duration, and severity of the electrographic seizure activity were age-dependent. No (sarin and VX) or brief (DFP) EEG seizure activity was evoked in PND14 rats, while SE progressively increased in severity as a function of age in PND21, 28 and 70 animals. Fluoro-Jade B staining was observed in multiple brain regions of animals that exhibited prolonged seizure activity. Neuronal injury in PND14 animals treated with DFP was lower than in older animals and absent in rats exposed to sarin or VX. In conclusion, we found that NAs and an OP provoked robust SE and neuronal injury similar to adults in PND21 and PND28, but not in PND14, rat pups. Convulsive behaviors were often present independent of EEG seizures and were unaccompanied by neuronal damage. These differential responses should be considered when investigating medical countermeasures for NA and OP exposure in pediatric populations.

View Accepted Manuscript (DOE)

Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0014664

OSTI ID:: 1623702

Journal Information:: Neurotoxicology, Journal Name: Neurotoxicology Journal Issue: C Vol. 66; ISSN 0161-813X

Country of Publication:: United States

Language:: English

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