Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication

Authors

Laxmikant Sudhir Deshpande, Virginia Commonwealth UniversityFollow
Dawn S. Carter, Virginia Commonwealth University
Kristin Phillips, Virginia Commonwealth UniversityFollow
Robert E. Blair, Virginia Commonwealth UniversityFollow
Robert J. DeLorenzo, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2014

Journal/Book/Conference Title

NeuroToxicology

Volume

44

First Page

17

Last Page

26

DOI of Original Publication

10.1016/j.neuro.2014.04.006

Comments

Originally published at doi:10.1016/j.neuro.2014.04.006.

Date of Submission

April 2015

Abstract

Paraoxon (POX) is an active metabolite of organophosphate (OP) pesticide parathion that has been weaponized and used against civilian populations. Exposure to POX produces high mortality. OP poisoning is often associated with chronic neurological disorders. In this study, we optimize a rat survival model of lethal POX exposures in order to mimic both acute and long-term effects of POX intoxication. Male Sprague–Dawley rats injected with POX (4 mg/kg, ice-cold PBS, s.c.) produced a rapid cholinergic crisis that evolved into status epilepticus (SE) and death within 6–8 min. The EEG profile for POX induced SE was characterized and showed clinical and electrographic seizures with 7–10 Hz spike activity. Treatment of 100% lethal POX intoxication with an optimized three drug regimen (atropine, 2 mg/kg, i.p., 2-PAM, 25 mg/kg, i.m. and diazepam, 5 mg/kg, i.p.) promptly stopped SE and reduced acute mortality to 12% and chronic mortality to 18%. This model is ideally suited to test effective countermeasures against lethal POX exposure. Animals that survived the POX SE manifested prolonged elevations in hippocampal [Ca²⁺]_i(Ca²⁺ plateau) and significant multifocal neuronal injury. POX SE induced Ca²⁺ plateau had its origin in Ca²⁺ release from intracellular Ca²⁺ stores since inhibition of ryanodine/IP₃ receptor lowered elevated Ca²⁺ levels post SE. POX SE induced neuronal injury and alterations in Ca²⁺ dynamics may underlie some of the long term morbidity associated with OP toxicity.

Rights

© 2014 Elsevier Inc. All rights reserved. NOTICE: this is the author’s version of a work that was accepted for publication in NeuroToxicology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in NeuroToxicology Volume 44, September 2014, Pages 17–26, doi:10.1016/j.neuro.2014.04.006.

Is Part Of

VCU Neurology Publications