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Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

Abstract

Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at {alpha}1- but is a high efficacy positive allosteric modulator at {alpha}5-containing GABA{sub A} receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here  More>>
Authors:
Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio; [1]  Auta, James [1] 
  1. Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States)
Publication Date:
Feb 27, 2009
Product Type:
Journal Article
Resource Relation:
Journal Name: Toxicology; Journal Volume: 256; Journal Issue: 3; Other Information: DOI: 10.1016/j.tox.2008.11.021; PII: S0300-483X(08)00566-0; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Subject:
54 ENVIRONMENTAL SCIENCES; ATROPINE; DAMAGE; DNA; HIPPOCAMPUS; HYPNOTICS AND SEDATIVES; LABELLING; LIABILITIES; LIGANDS; NERVE CELLS; POISONING; RATS; RECEPTORS; TELEMETRY
OSTI ID:
21181384
Country of Origin:
Ireland
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0300-483X; TXCYAC; TRN: IE09R0149055611
Availability:
Available from http://dx.doi.org/10.1016/j.tox.2008.11.021;INIS
Submitting Site:
INIS
Size:
page(s) 164-174
Announcement Date:
Jul 17, 2009

Citation Formats

Kadriu, Bashkim, Guidotti, Alessandro, Costa, Erminio, and Auta, James. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage. Ireland: N. p., 2009. Web. doi:10.1016/j.tox.2008.11.021.
Kadriu, Bashkim, Guidotti, Alessandro, Costa, Erminio, & Auta, James. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage. Ireland. doi:10.1016/j.tox.2008.11.021.
Kadriu, Bashkim, Guidotti, Alessandro, Costa, Erminio, and Auta, James. 2009. "Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage." Ireland. doi:10.1016/j.tox.2008.11.021. https://www.osti.gov/servlets/purl/10.1016/j.tox.2008.11.021.
@misc{etde_21181384,
title = {Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage}
author = {Kadriu, Bashkim, Guidotti, Alessandro, Costa, Erminio, and Auta, James}
abstractNote = {Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at {alpha}1- but is a high efficacy positive allosteric modulator at {alpha}5-containing GABA{sub A} receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a higher dose of diazepam is required to produce similar protective effects. These finding suggests that imidazenil, a non-sedating anticonvulsant BZ ligand, is a more potent, effective, and safer drug than diazepam in protecting rats from DFP-induced seizures and the associated neuronal damage and/or ongoing neuronal degeneration.}
doi = {10.1016/j.tox.2008.11.021}
journal = {Toxicology}
issue = {3}
volume = {256}
place = {Ireland}
year = {2009}
month = {Feb}
}