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Research ArticleDrug Discovery and Translational Medicine

Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

James P. Apland, Vassiliki Aroniadou-Anderjaska, Taiza H. Figueiredo, Carol E. Green, Robert Swezey, Chun Yang, Felicia Qashu and Maria F. M. Braga
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 133-140; DOI: https://doi.org/10.1124/jpet.112.198689
James P. Apland
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Vassiliki Aroniadou-Anderjaska
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Taiza H. Figueiredo
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Carol E. Green
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Robert Swezey
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Chun Yang
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Felicia Qashu
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Maria F. M. Braga
US Army Medical Research Institute of Chemical Defense, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, Maryland (J.P.A.); Departments of Anatomy, Physiology and Genetics (V.A.-A., T.H.F., F.Q., M.F.M.B.) and Psychiatry (V.A-A., M.F.M.B.), F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and Biosciences Division of SRI International, Menlo Park, California (C.E.G., R.S., C.Y.)
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Abstract

Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood–brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound.

Footnotes

  • This work was supported by the CounterACT Program, National Institutes of Health, Office of the Director; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant 5U01NS058162-07], and the Defense Threat Reduction Agency-Joint Science and Technology Office, Medical S&T Division [Grant CBM.NEURO.01.10.US.18 and CBM.NEURO.01.10.US.15].

  • dx.doi.org/10.1124/jpet.112.198689.

  • Received August 13, 2012.
  • Accepted October 4, 2012.
  • U.S. government work not protected by U.S. copyright.
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleDrug Discovery and Translational Medicine

LY293558 Pharmacokinetics and Efficacy against Soman

James P. Apland, Vassiliki Aroniadou-Anderjaska, Taiza H. Figueiredo, Carol E. Green, Robert Swezey, Chun Yang, Felicia Qashu and Maria F. M. Braga
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 133-140; DOI: https://doi.org/10.1124/jpet.112.198689

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Research ArticleDrug Discovery and Translational Medicine

LY293558 Pharmacokinetics and Efficacy against Soman

James P. Apland, Vassiliki Aroniadou-Anderjaska, Taiza H. Figueiredo, Carol E. Green, Robert Swezey, Chun Yang, Felicia Qashu and Maria F. M. Braga
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 133-140; DOI: https://doi.org/10.1124/jpet.112.198689
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