title: 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 62μg/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 2mg/kg, administered 20 min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/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 1h 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 90days 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 1h post-exposure, prevents brain pathology and behavioral deficits.
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: stevenmiller17@gmail.com.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Miller
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: vanderjaska@usuhs.edu.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aroniadou-Anderjaska
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: taiza.figueiredo.ctr@usuhs.edu.
authors.forename: Taiza H
authors.initials: TH
authors.lastname: Figueiredo
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: eric.prager683@gmail.com.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Prager
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: camilapalmeida@gmail.com.
authors.forename: Camila P
authors.initials: CP
authors.lastname: Almeida-Suhett
authors.affiliation: Neurotoxicology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. Electronic address: james.p.apland.civ@mail.mil.
authors.forename: James P
authors.initials: JP
authors.lastname: Apland
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Electronic address: maria.braga@usuhs.edu.
authors.forename: Maria F M
authors.initials: MF
authors.lastname: Braga
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy; D010091:Oximes / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000110:Acetylcholinesterase; D000927:Anticonvulsants; D001285:Atropine; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D007546:Isoquinolines; D010091:Oximes; D018092:Kainic Acid Receptors; D012999:Soman; D013777:Tetrazoles; C082309:tezampanel
keywords: Acetylcholinesterase; Atropine sulfate; GluK1 antagonists; Immature rats; Seizures; Soman