Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning

Frontiers in Pharmacology. 2019;10 DOI 10.3389/fphar.2019.00560

 

Journal Homepage

Journal Title: Frontiers in Pharmacology

ISSN: 1663-9812 (Online)

Publisher: Frontiers Media S.A.

LCC Subject Category: Medicine: Therapeutics. Pharmacology

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML, ePUB, XML

 

AUTHORS


Timothy B. C. Johnstone (Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, United States)

Hilary S. McCarren (Neuroscience Department, Medical Toxicology Research Division, United States Army Research Institute of Chemical Defense, Aberdeen, MD, United States)

Jay Spampanato (Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, United States)

F. Edward Dudek (Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, United States)

John H. McDonough (Neuroscience Department, Medical Toxicology Research Division, United States Army Research Institute of Chemical Defense, Aberdeen, MD, United States)

Derk Hogenkamp (Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, United States)

Kelvin W. Gee (Department of Pharmacology, School of Medicine, University of California, Irvine, Irvine, CA, United States)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 14 weeks

 

Abstract | Full Text

Seizures induced by organophosphorus nerve agent exposure become refractory to treatment with benzodiazepines because these drugs engage synaptic γ-aminobutyric acid-A receptors (GABAARs) that rapidly internalize during status epilepticus (SE). Extrasynaptic GABAARs, such as those containing α4β3δ subunits, are a putative pharmacological target to comprehensively manage nerve agent-induced seizures since they do not internalize during SE and are continuously available for activation. Neurosteroids related to allopregnanolone have been tested as a possible replacement for benzodiazepines because they target both synaptic and extrasynaptic GABAARs receptors. A longer effective treatment window, extended treatment efficacy, and enhanced neuroprotection represent significant advantages of neurosteroids over benzodiazepines. However, neurosteroid use is limited by poor physicochemical properties arising from the intrinsic requirement of the pregnane steroid core structure for efficacy rendering drug formulation problematic. We tested a non-steroidal enaminone GABAAR modulator that interacts with both synaptic and extrasynaptic GABAARs on a binding site distinct from neurosteroids or benzodiazepines for efficacy to control electrographic SE induced by diisopropyl fluorophosphate or soman intoxication in rats. Animals were treated with standard antidotes, and experimental therapeutic treatment was given following 1 h (diisopropyl fluorophosphate model) or 20 min (soman model) after SE onset. We found that the enaminone 2-261 had an extended duration of seizure termination (>10 h) in the diisopropyl fluorophosphate intoxication model in the presence or absence of midazolam (MDZ). 2-261 also moderately potentiated MDZ in the soman-induced seizure model but had limited efficacy as a stand-alone anticonvulsant treatment due to slow onset of action. 2-261 significantly reduced neuronal death in brain areas associated with either diisopropyl fluorophosphate- or soman-induced SE. 2-261 represents an alternate chemical template from neurosteroids for enhancing extrasynaptic α4β3δ GABAAR activity to reverse SE from organophosphorous intoxication.