title: The limitations of diazepam as a treatment for nerve agent-induced seizures and neuropathology in rats: comparison with UBP302.
abstract: Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl)willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: James P
authors.initials: JP
authors.lastname: Apland
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aroniadou-Anderjaska
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Taiza H
authors.initials: TH
authors.lastname: Figueiredo
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Franco
authors.initials: F
authors.lastname: Rossetti
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Miller
authors.affiliation: Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (J.P.A.); and Department of Anatomy, Physiology, and Genetics (V.A.-A., T.H.F., F.R., S.L.M., M.F.M.B.) and Department of Psychiatry (V.A.-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland maria.braga@usuhs.edu.
authors.forename: Maria F M
authors.initials: MF
authors.lastname: Braga
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D012999:Soman / Q000009:adverse effects; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000409:Alanine; D000927:Anticonvulsants; D003975:Diazepam; D018092:Kainic Acid Receptors; D012999:Soman; D013941:Thymine; C509618:1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione